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Familial and late-onset Alzheimer’s disease: Evidence for an auto-immune component triggered by viral, microbial and allergen antigens with homology to beta-amyloid and APP mutant peptides. by Chris Carter is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

C.J.Carter:

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 Abstract

 

            Autoantibodies to beta-amyloid are common in the ageing population and in Alzheimer’s disease and may derive from aberrant forms of beta-amyloid (Abeta) or from antigens with homology to it. The latter seems likely, as glycoprotein B of the Herpes simplex virus (HSV-1) and 69 other viruses and phages, including HHV-6, Hepatitis C, polyoma viruses and HIV-1 show exact homology with a VGGVV C-terminal fibrillogenic sequence, an epitope that labels beta-amyloid in the Alzheimer’s disease brain. Other viruses, including those causing the common cold and influenza also show significant homology with known and predicted beta amyloid epitopes, as do a number of allergens (food, pollen and insect venoms and most notably house dust mites). Bacteria implicated as risk factors in Alzheimer’s disease (C.Pneumoniae, B.Burgdorferri , H.Pylori, P.Gingivalis) also contain matching Abeta proteins as does the meningitis causing fungus, C.Neoformans, which has been associated with a rare but curable misdiagnosed form of Alzheimer’s disease. Immune activation occurs in the Alzheimer’s disease brain, as evidenced by many immune-related proteins in plaques and by the presence of the complement membrane attack complex in neurones. These observations suggest that Alzheimer’s disease is an autoimmune disorder triggered by pathogens with homology to beta-amyloid, whose antibodies target and kill the neurones within which the peptide resides, via immune and inflammatory activation and complement-related lysis. Viruses matching the Abeta target regions of beneficial catalytic autoantibodies include those from components of the Mediterranean diet (plant viruses) and from the papillomavirus and other cancer-inducing viruses, both of which (cancer and diet) are inversely associated with Alzheimer’s disease risk. As a vaccine against the human papillomavirus already exists, it may have a role to play in the prevention of Alzheimer’s disease. This scenario explains most of the epidemiological observations in Alzheimer’s disease which is more common in women and Afro-Americans, as is HSV-2 seroprevalence; related to the number of pregnancies and thus greater exposure to childhood infections, and less severe in nuns, who are shielded from sexually transmitted diseases. Atopy and autoimmune disorders are common in Alzheimer’s disease in accord with allergen homology to Abeta, and the use of anti-inflammatory agents has been reported to reduce the risk of developing Alzheimer’s disease. HIV-1 infection can cause dementia with Alzheimer’s disease pathology, again in accord with Abeta homology. The four major risk genes in Alzheimer’s disease, APOE, clusterin, complement receptor 1 and PICALM can all be related to viral life cycles and clusterin and complement receptor 1 are both complement inhibitors. This scenario is also relevant to familial Alzheimer’s disease, as the four mutant forms of APP717  and the Swedish mutant (APP670/671) convert the surrounding peptide to matches with commensal bacterial flora (E.Coli, E. Faecalis, P.Gingivalis) and to viruses with high seroprevalence (HHV-6, norovirus and polyoma viruses) and to those causing influenza and the common cold. Multiple lines of evidence thus suggest that late-onset and Familial Alzheimer’s disease are autoimmune disorders caused by diverse common pathogens and allergens that are homologous to beta-amyloid or mutant APP fragments. Antibodies to these multiple agents are a likely source of the autoantibodies to beta-amyloid in the ageing population and would accumulate with repeated antigen exposure and age, the greatest risk factor in Alzheimer’s disease. Vaccination, which has already been shown to reduce the incidence of Alzheimer’s disease (diphtheria, influenza, tetanus, and polio), pathogen screening and elimination, and immunosuppressant therapy may be of therapeutic benefit in this disorder. This scenario is also relevant to several other autoimmune disorders including multiple sclerosis, myasthenia gravis,  pemphigus vulgaris, systemic lupus erythematosus, and Chronic obstructive pulmonary disease where the known autoantigens also line up with the reported viral risk factors. Mutant proteins from other genetic diseases (Huntington’s disease and other PolyGlutamine repeat disorders) and cystic fibrosis also align with very common viruses. This may well be a near universal phenomenon, reflecting the idea that all life evolved from viruses, which have however left behind a deadly legacy of human viral derived proteins with homology to antigenic regions of the current virome. This could well be responsible for most of our ills. This also suggests that vaccination using epitopes to the non-homologous regions of the viral culprits may be of benefit in autoimmune and even in human genetic disorders.

 

 

 

Introduction

 

            Autoantibodies to beta-amyloid are common in the ageing population and in Alzheimer’s disease and may exert a beneficial role in adsorbing the toxic peptide or catalysing its destruction. They may also mount an immune attack against beta-amyloid, activating inflammatory pathways and complement cascades that kill the neurones in which the peptide resides (1-3) . The membrane attack complex of the complement pathway is present in Alzheimer’s disease neurones (4;5) , supporting a role for aberrant immune/complement activation within the brain. The source of these autoantibodies is not clear. They could be derived as a response to abnormal forms of beta-amyloid or from antibodies to other antigens that cross-react with the peptide.

            It has already been noted that glycoprotein B of the Herpes simplex virus shows marked homology with beta-amyloid, particularly matching a VGGVV C-terminus pentapeptide (6) (Fig 1). The VGGVG epitope has been used to label beta-amyloid1-40 in extracellular neurofibrillary tangles (7) . This pentapeptide, per se, forms aggregates characterised by twisted ropes and banded fibrils (8) . This is a characteristic of both beta-amyloid and of HSV-1 glycoprotein B peptide fragments containing this sequence. The viral glycoprotein B fragments form thioflavine T positive fibrils which accelerate beta-amyloid fibril formation, and are neurotoxic in cell culture (9) .Herpes simplex infection (HSV-1) has been shown to be a risk factor in Alzheimer’s disease, acting in synergy with possession of the APOE4 allele (10) . HSV-1 infection in mice or neuroblastoma cells increases beta-amyloid deposition and phosphorylation of the microtubule protein tau (11;12) .Viral infection in mice also results in hippocampal and entorhinal cortex neuronal degeneration and memory loss,  all as found in Alzheimer’s disease (13) . A recent study has also shown that anti-HSV-1 immunoglobulin M seropositivity, a marker of primary viral infection or reactivation, in a cohort of healthy patients, was significantly associated with the subsequent development of Alzheimer’s disease. Anti-HSV-1 IgG, a marker of lifelong infection showed no association with subsequent Alzheimer’s disease development (14) . All of these factors support a viral influence on the development of Alzheimer’s disease. Antibodies to the Potato virus Y, which is highly homologous to beta-amyloid (Fig 1), are also able to label beta-amyloid containing plaques in the Alzheimer’s disease brain (15) . It is therefore possible that beta-amyloid autoantibodies are derived from such homologous antigens. Homology searches within viral and microbial proteomes and allergenic proteins showed that many are highly homologous to immunogenic regions of the beta-amyloid peptide and also that APP mutations in Familial Alzheimer’s disease convert the surrounding peptides to matches to very common viruses and bacteria.

 

Methods

 

            Homology searches against viral, bacterial or fungal proteomes were performed via the NCBI or Uniprot BLAST servers and sequence alignments via the CLUSTAL server at UniProt (16) . Homology with allergen sequences was determined by interrogation of the Structural database of Allergenic Proteins (17) http://fermi.utmb.edu/SDAP/index.html and from homology searches at the AllergenOnLine database http://www.allergenonline.org/ (18) . Epitopes containing viral/beta amyloid matching sequences were found using the Human Immune epitope database. www.immuneepitope.org (19) . B-Cell epitopes were identified using the BepiPred server http://www.cbs.dtu.dk/services/BepiPred/ (20) .

 

 

Results

 

            The homology between HSV-1 glycoprotein B and beta-amyloid1-42 is  shown in Fig 1. A homology search against viral proteomes showed that a number of other viruses contain this VGGVV sequence (Table 1). These include  adenovirus 8, Dengue virus, Herpes Simplex (HSV-1, 2 and 6)  hepatitis C,  Lactate dehydrogenase-elevating virus, the polyoma virus and HIV-1, viruses infecting family pets (cats, guinea pigs and goldfish) and farmyard animals (cattle,  horses, pigs and poultry) and viruses infecting certain foodstuffs (cherries, radish, strawberries and raspberries, tomatoes, potatoes, watermelon, oysters, salmon and shrimp). The VVGGV sequence is also present in a number of phages infecting bacteria that cause common childhood and adult diseases (Gastroenteritis, food poisoning, hospital infections (nococosmial), and wound infections).  It should be noted that the VGGVV sequence was restricted to 69 viruses and phages (Table 1) out of 2463 viral genomes in the NCBI database.

A further homology search against the viral proteome database revealed that many other common viruses express proteins with marked homology (pentapeptides or more) to other sequences within the beta-amyloid peptide (Table 2). These viruses include Adenovirus D, Coxsackie virus B2, influenza, hepatitis C and Yellow fever, numerous HIV-1 or HIV-2 proteins, and the human papillomavirus. Bovine and poultry viruses were also well represented. Phages infecting campylobacter, enterobacteria, lactococcus, mycobacterium, streptococci and vibrio  (Pentapeptide or more) as well as Listeria and pseudomonas (Tetrapeptide matches) were also represented . These infect very common benign or infection-related bacteria. Although less homologous, viruses causing the common cold, mumps, rubella and polio nevertheless contained exactly matching tetrapeptide beta-amyloid sequences.

Numerous plant viruses contain both the VGGVV and other matching beta-amyloid sequences. Plant viruses are generally considered as benign or unable to infect humans.  However, they are obviously ingested and exist in human faeces (21) . The Pepper mottle virus has recently been associated with fever in Man (22) suggesting that phytonosis might be more common than thought. A capsid protein of this virus contains the YEVHHQ sequence of beta-amyloid as do a number of other plant viruses, including the potato virus. This sequence is immunogenic (in beta-amyloid) and antibodies to the potato virus label amyloid plaques in the Alzheimer’s disease brain (15) . Sequences within the potato virus polyprotein show 54% identity with beta-amyloid1-28 (Fig 1).

Many of the viruses containing beta-amyloid sequences are very common (eg influenza and Herpes viruses and even the common cold virus) and the beta-amyloid matching phages are associated with a number of bacteria causing common gastrointestinal problems (e.g. clostridum, salmonella and vibrio) or associated with hospital infections (Pseudomonas, Serratia). Exposure to these agents, which possess myriad strains, is ineluctable and each exposure is likely to increase the risk of generating antibodies that might also target the beta-amyloid peptide.

 

Bacteria and Fungi implicated in Alzheimer’s disease

 

            The VGGVV sequence, and others, are also present in proteins from C.Pneumoniae, Borrelia Burgdorferri and Helicobacter pylori (Table 3) all of which have been implicated as risk factors in Alzheimer’s disease (23;24) . Indeed, in infected Alzheimer’s disease patients, H.Pylori eradication can have beneficial effects on cognition (25) . C.Pneomoniae (penta- and hexapeptides) B.Burgdorferri (pentapeptides) and H.Pylori (Penta- and hexapeptides) proteins all contain matching beta-amyloid fragments. Tooth loss and periodontitis have also been cited as risk factors in Alzheimer’s disease (26;27) . Porphyromonas gingivalis and Streptococcus mutans are major cause of periodontitis, and proteins from these bacteria also contain the VGGVV and other internal beta-amyloid sequences (Table 3).

There are two case reports in the literature recording subjects diagnosed with Alzheimer’s disease, both with a three year history of dementia. Cryptococcal meningitis was subsequently diagnosed, and in both cases, antifungal treatment resulted in an almost complete recovery (28;29)  C.Neoformans  is the agent responsible for Cryptococcal meningitis and contains a number of proteins showing a striking similarity with beta-amyloid internal sequences, including exact homology with an N-terminus octapeptide and a c-terminus heptapeptide as well as the VGGVV sequence (Table 3).

           

Allergenic proteins

 

 A search of the allergen databases showed that stretches within the beta-amyloid peptide, exactly match those in several common allergens, particularly in European (hexapeptide) and American (pentapeptide) house dust mites (Table 2, Fig 3 ) and in  a rice fungus Aspergillus Oryzae. Rather less pentapeptide or more  matches were found in this class but very many common pollen, fungal , insect venom, domestic animal (cat, cattle and horse) and food allergens (beans, rice, potato, tomato and nuts ) contain tetrapeptide sequences matching those of beta amyloid . House dust mites, as well as containing relatively large consensual sequences, display a large number of smaller peptide matches along the length of the beta-amyloid peptide (Table 2) suggesting that these ubiquitous and unavoidable creatures could play a rather unexpected role in Alzheimer’s disease.

 

Immune activation in the Alzheimer’s disease brain

 

            A number of immune-system related proteins are found in amyloid plaques or neurofibrillary tangles. Interleukin 1 alpha, interleukin 6, and tumor necrosis factor are all been localised within plaques (30) and acute phase proteins involved in inflammation, such as amyloid P, alpha-1 antichymotrypsin and C-reactive protein are also plaque components (31) while Immunoglobulin G is located in the plaque corona (32) . Large increases in IgG levels have been recorded in the brain parenchyma, in apoptotic dying neurones and in cerebral blood vessels in the Alzheimer’s disease brain (33) . Complement component C3 is found in Alzheimer’s disease amyloid plaques along with complement C4 (34) . Complement components Clq, C3d, and C4d are present in plaques, dystrophic neurites and neurofibrillary tangles (5) . 

The membrane attack complex (MAC), composed of complement proteins C5 to C9, forms a channel that is inserted into the membranes of pathogens, destroying them by lysis. These components cannot be detected in temporal cortex amyloid plaques in Alzheimer’s disease  (34;35) . However the MAC complex is present in dystrophic neurites and neurofibrillary tangles (5) and others have detected this complex in neuritic plaques and tangles, along with deposition of C1q, C3 and clusterin (36) . The membrane attack complex has also been detected in the neuronal cytoplasm in AD brains and associated with neurofibrillary tangles and lysosomes (4) .The presence of the MAC complex in neurones might suggest that neuronal lysis by the MAC complex could contribute to neuronal cell death (5) .

 

Pathogen seropositivity in Alzheimer’s disease

 

            Increased seropositivity to IgM anti HSV-1 antibodies has been reported to predict the risk of subsequently developing Alzheimer’s disease (14) . Increased seropositivity in Alzheimer’s disease has also been reported for Helicobacter pylori (37) and increased HHV-6 immunoreactivity has been observed in Alzheimer’s disease CSF samples (38) . No differences in the seropositivity of Adenovirus, Chlamydia Group B, Coxiella burnettii, Cytomegalovirus, Herpes simplex virus, Influenza A, Influenza B, Measles and Mycoplasma pneumoniae were found in a study of 33 Alzheimer’s disease patients and 28 controls (39) . However, there are a large number of diverse pathogenic antigens with homology to beta-amyloid, any of which may have been present, potentially provoking immune response-related neuronal loss, many years prior to seropositivity testing.   

 

 

Antibodies and antigenicity

 

            The tenet of the autoimmune hypothesis is that viral and other pathogens and environmental allergens with homology to beta-amyloid will trigger the production of antibodies that also target the beta-amyloid peptide. Those provoking a robust immune, inflammatory and complement response risk killing beta-amyloid containing neurones. Antibodies to the Potato virus (15) and to Borrelia antigens (24) ) have already been shown to label amyloid plaques in the Alzheimer’s disease brain and antibodies to a phage epitope (AEFRH) also label beta-amyloid (40) . 

            Potential cross-reactivity can partly be tested in silico but ultimately requires the characterisation of the autoimmune beta-amyloid epitopes present in Alzheimer’s disease and cross-reactivity testing between pathogenic and environmental antigens and beta-amyloid. Thus far, the precise epitopes labelled by beta-amyloid autoantibodies have not been fully characterised.

            The initial rendezvous of antigens with the immune system is with B-cells which bind to, engulf and digest the antigen. The B-cell epitope antigenicity prediction (20) for beta-amyloid is illustrated in Figs 2 and 3, over which are laid the pathogens and allergens that match particular sequences within the beta-amyloid peptide. As can be seen, Coxsackie, HIV-1, HSV-1, Hepatitis C, influenza, mumps, the respiratory syncitial virus, rhinoviruses (common cold) and clostridia, enterobacteria and vibrio phages match sequences that lie within predicted antigenic regions of beta-amyloid (Fig 2). An increase in immunogenicity is also observed within the VGGVV sequence, which has been used as an epitope to label beta-amyloid (7) . Allergenic proteins whose sequences match those of antigenic portions of beta-amyloid include those from fungal, nut, pollen, insect venom and house dust mites (Table 2, Fig 2).

            As a further theoretical test, all consecutive tetrapeptide sequences within beta-amyloid were screened against the human epitope and the HIV-1 molecular Immunology databases to determine which antigens contain these epitopes. As shown in Tables 2 to 7 many viral, fungal, bacterial, parasite and allergen antibodies contain tetrapeptide sequences from the beta-amyloid peptide. In addition, apart from beta-amyloid isoforms and a small number of mammalian proteins, the major matching epitopes were concentrated in viral, bacterial, fungal and allergen classes (i.e. not other species or other mammalian proteins). These databases contain over 73,000 epitopes, so again the results returned are highly specific to these classes. This at least shows that antibodies that have been used to label these viruses, pathogens and allergens, contain beta-amyloid sequences, and that potential cross-reacting antibodies are concentrated in these classes.

            The ability of autoantibodies to adsorb beta-amyloid can be considered as useful, and certain of these appear to be associated with reduced plaque volume (1) . Other autoantibodies, present in normal and Alzheimer’s disease sera, also possess catalytic properties and are capable of destroying the toxic peptide. Such antibodies do not form stable immune complexes and are less likely to activate immune inflammatory and complement related cell lysis (2) . This is where the danger lies, as antibodies capable of mounting a full-blown immune response against beta-amyloid are likely to kill the cells in which the peptide resides. It is relatively common to find Alzheimer’s disease pathology at autopsy (plaques and tangles) in patients who were cognitively normal shortly before death (41) . In such patients, it is tempting to suggest that immune-activating antibodies are rare.

            Catalytic beta-amyloid auto-antibodies cleave the beta-amyloid peptide primarily between the two histidines (H/Q) at Abeta13-14 , and to a lesser extent at other positions as shown in Figs 2 and 3 {Taguchi, Planque, et al. 2008 1720 /id} . The major cleavage site is within a non-immunogenic region of the peptide. Interestingly, several plant viruses (Amaranthus, Pepper, Pistachio, Potato, Rice, Soybean, Sunflower and Zucchini (courgette) and allergens (Rice, Pistaccio, Soybean as well as the cat allergen and insect venoms)  express proteins homologous to this particular region. Rather intriguingly, several of these plants/vegetables are constituents of the Mediterranean diet which has been reported to reduce the risk of developing Alzheimer’s disease (42) . Such diets impact on cholesterol/lipoprotein function and on atherosclerosis, a major contributory factor in Alzheimer’s disease  (43;44) but could also conceivably be related to beneficial antibodies generated by the ingestion of common plant viruses, a possibility that also suggests potential immunisation strategies.

            Certain proteins from three cancer-causing viruses, Epstein-Barr (HSV-4), Hepatitis B and the human Papillomavirus virus are also homologous to this catalytic antibody target region, suggesting a plausible explanation for the inverse association between cancer and Alzheimer’s disease (45)     

 

Vaccinations and Alzheimer’s disease

 

            It has been noted that the risk of developing Alzheimer’s disease was reduced following vaccination against diphtheria, influenza, polio or tetanus (46) . Again, sequences within proteins of these pathogens are homologous to beta-amyloid as shown in Fig 2, (which represents the viral proteins rather than the epitopes used for vaccination). This is rather encouraging as it suggests that, if the effect of vaccination is due to beta-amyloid homology, other vaccines might similarly reduce the incidence of Alzheimer’s disease. The papillomavirus vaccine, already used to prevent cervical cancer (47) , is a prime candidate as a viral protein matches the beta-amyloid region targeted by catalytic autoantibodies. However, as there is an evident danger of creating potentially toxic beta-amyloid autoantibodies, characterisation of the epitopes targeted by such vaccines must be of prime concern.

 

Epidemiological studies

 

            These observations suggest that Alzheimer’s disease may have an autoimmune component, triggered by antigenic proteins with homology to beta-amyloid. Such a scenario helps to explain several, indeed most, epidemiological features of Alzheimer’s disease. For example, Atopy and autoimmune diseases are common in Alzheimer’s disease (48;49)   , and could relate to allergen homology with beta-amyloid. Alzheimer’s disease prevalence is higher in women and in Afro-Americans (50) , as is HSV-2 prevalence (51) .

            . Herpes simplex infection is a risk factor in Alzheimer’s disease acting in synergy with the APOE4 allele (52) and dementia, with Alzheimer’s disease pathology is common in HIV-1 infected patients (53) , a situation perhaps explained by viral protein homology with beta-amyloid. Such homology with pathogen proteins could also explain the association of Borrelia Burgdorferri, Helicobacter pylori, C.Pneumoniae (23;24)  and by inference P.Gingivalis and Streptococcus mutans (oral pathogens causing periodontitis and tooth loss (26;27)  ) with Alzheimer’s disease. The incidence of Alzheimer’s disease is also related to the number of pregnancies (54) , which might be explained by greater exposure to common childhood illnesses (cf phage/bacterial homology with beta-amyloid). It has also been noted that nuns, who are less exposed to sexually transmitted pathogens, show some resistance to the ravages of Alzheimer’s disease (41) . An autoimmune scenario may also explain why the use of non-steroidal anti-inflammatories reduces the risk of developing Alzheimer’s disease (55) as do fish consumption and the Mediterranean diet (42;56) .Such diets are rich in N-3 polyunsaturated fatty acids, which also possess anti-inflammatory properties (57) . The beneficial effects of these diets and also of statins (58) are likely to be related to multiple problems in cholesterol and lipoprotein homoeostasis in Alzheimer’s disease (59) but may also be related to pathogens and the immune system. For example viral entry is often lipid dependent a a factor related to fusion of the viral lipid envelope with cell membranes, and the cellular entry of HIV-1 and herpes simplex is cholesterol and lipid raft -dependent and blocked by nystatin (60;61) . Statins also habe immunosuppressant properties (62) . The potential role of viruses as constituents of the Mediterranean diet has been discussed above in relation to their homology with beta-amyloid regions targeted by beneficial catalytic autoantibodies. The inverse association between cancer and Alzheimer’s disease might also be explained in these terms (see above) and the beneficial effects of vaccination can also be related to pathogen homology with beta-amyloid (diphtheria, influenza, tetanus and polio). The risk promoting effects of aluminium in Alzheimer’s disease (63) might also be explained by its common self-prescribed use as an antacid in gastrointestinal disturbances (64) often caused by phage/bacterial pathogens with homology to beta-amyloid.

            In short almost all epidemiological observations related to Alzheimer’s disease can be explained in terms of pathogens and/or autoimmunity.

 

 

Late-onset Alzheimer’s disease susceptibility genes           

           

Four genes, Apolipoprotein E, clusterin, complement receptor 1 and PICALM, are the main suspects in Alzheimer’s disease (65-67)  each of which can be implicated in viral life cycles. For example, APOE binds to HSV-1 (68) and Hepatitis C viruses (69) and the Alzheimer’s disease risk allele, APOE4, is also related to HSV-1 and HIV-1 infection, although, curiously, it protects against Hepatitis C infection (70) .  Complement receptor 1 and clusterin are both involved in the complement cascades that play a crucial role in pathogen defence (71) . In addition the influenza virus and HSV-1 both bind to complement receptor 1 on erythrocytes (72) . One of the receptors used by Herpes simplex for cellular entry is the Mannose-6-phosphate receptor, M6PR (73) . This receptor binds to clusterin (74) and its traffic through the endosomal compartments is controlled by PICALM, whose overexpression reduces M6PR localisation in endosomes, suggesting blockade of its transport from the plasma membrane or the trans-golgi network (75) . The Herpes simplex and Influenza viruses also uses exportin (Crm1) dependent pathways for nuclear egress (76;77) . PICALM and other endocytic-regulatory proteins bind to Crm1 (78) .

Many minor genes (see www.polygenicpathways.co.uk/alzpolys for references) are also implicated in viral life cycles. For example lipoprotein receptors implicated in Alzheimer’s disease (LRP1, LDLR, VLDLR) are used by human rhinoviruses to gain cellular entry (79) . The nectin receptor PVRL2 is a Herpes viral receptor (80) , as is insulin degrading enzyme (81) .  In addition over 30 immune related genes (chemokines, cytokines, complement related, toll receptors HLA-antigens) have been implicated as risk factors. All of these might be expected to modulate immune defence.

            Given the plethora of viral and environmental beta-amyloid homologues, and the presence of autoantibodies to beta-amyloid in healthy aged subjects, it seems likely that the functional gene variants in the control group, rather than the Alzheimer’s disease risk promoting genes, may be more important.  These are presumably those that prevent the ravages of autoimmunity.

 

Familial Alzheimer’s disease

 

            Familial early-onset Alzheimer’s disease is caused by a number of different mutations in presenilins and  the APP gene, including several mutations as APP717  (V/I, V/M, V/G, V/L) (London mutation and others) and at KM670/671NL (Swedish mutation) (inter alia :see http://www.molgen.ua.ac.be/ADMutations/)  (82) . These are not within the beta-amyloid sequence. Both mutations modify APP processing and increase the generation of Abeta 1-42 (83;84) . In so doing, they may thus be able to increase the probability of Abeta encountering autoantibodies, both in the brain and in the periphery resulting in a feed forward further generation of autoantibodies by the immune system.

            The APP717 mutant is within two gamma-secretase cleavage sites generating an undecapeptide as shown in Fig 1. The Swedish mutation is immediately prior to the beta-secretase cleavage site that, with gamma-secretase, generates beta-amyloid and frees the native or mutant APP670/671 terminus (85) . Homology searches against viral and bacterial proteomes were performed using the native and mutant forms of the APP717 undecapeptide and the nonapaptide upstream of the Swedish mutation sites (Fig 1).  The APP717G mutant increased the predicted B-type immunogenicity of the peptide, but other mutants were without effect (not shown). 

            Native APP717 is homologous to several phages, viruses and bacteria, many of which are common; for example Enterobacteria, lactococcus and staphylococcus phages, adenovirus, cytomegalovirus, the parainfluenza virus and  rotavirus and the less common rabies and coronaviruses (Table 4).  This native form also shows homology with several bacterial species, which for the most part, with the exception of Lactobacilli, are pathological rather than commensal (Table 5).

            The various APP717 mutations alter this matching profile in a number of ways. For example the V/F mutation creates matching peptides to Herpes viruses HSV-2, 3 and 8 and markedly increases the number of hits in relation  to homology, particularly within bacterial flora (mainly due do many strains of the commensal E.Faecalis) (Tables 4 and 5).

            The APP717 V/G mutant creates a peptide region homologous to proteins from human herpes virus 6, a pathogen with seroprevalence approaching 100% (86) and to the JC and BK polyomaviruses which also display high seroprevalence in the normal population ( 39% and 82% respectively (87) ) . This mutant also creates regions homologous to the endemic soil bacterium B.Cereus, to a bacterium causing verrucas, and to P.Gingivalis a constituent of the oral flora that plays a role in periodontitis and tooth loss (tables 4 and 5).

            The V/I mutant creates homologues to proteins from over 30 Rhinococcal strains causing the common cold, to the mumps virus and to the common Norovirus responsible for vomiting sickness, as well as to the endemic soil bacteria B.Cereus and S.Aureus, and the commensal E.Coli and P.Gingivalis (Table 4,5).

The V/L mutant creates regions homologous to proteins from Influenza A and B viruses and to Hepatitis C and Herpes viruses 4 and 5, as well as to the commensal E.Coli and Streptococcus Hominis (Tabke 4,5).

            The native APP670/671 peptide is homologous to a number of influenza viruses, which are almost exclusively avine. The Swedish mutant increase the number of viral matches to the upstream peptide, particularly to enterobacterial phages, and creates homologous regions to several species of human adenoviruses, which also show high seroprevalence (88) , and to the respiratory syncitial virus as well as to human rhinoviruses and again to E.Coli. Several of these mutant peptides are homologous to mycobacterial phages (see Tables 6,7 ), perhaps explaining why tuberculosis (as well as possession of the HLA-DR3 allele) have been reported as risk factors in familial Alzheimer’s disease (49) . The epitopes generated by these mutants are again concentrated within viral and pathogen proteins, particularly the Vaccinia Virus (Tables 4-7). There do not appear to have been any studies on autoantibodies in familial Alzheimer’s disease but the large number of viral and bacterial peptides perfectly matching the mutant surrounds suggests that autoimmunity may also play a major role in this disorder. Although clearly genetic, its pathology may be autoimmune related, as well as to, or perhaps rather than aberrant beta-amyloid processing.

            In short, these mutants, in different ways, all increase the number and variety of viral and bacterial matches, to commensal (Particularly E.Coli, E.Faecalis and P.Gingivalis ) as well as to pathological species (Clostridia, Mycobacteria, Vibrio, inter alia)  and create homologous regions to very common pathogens causing the common cold, influenza, herpes infections and periodontitis.

           

APP transgenic mice

 

            If autoimmunity rather than problems in APP processing is relevant, this could explain why APP transgenic models do not faithfully mimic Alzheimer’s disease (i.e. extensive cholinergic neuronal loss, loss of hippocampal afferents and efferents and massive cortical degeneration) (89) . There have been two studies assessing the effects of infection in APP transgenic mice. Repeated Streptococcus Pneumoniae infection had no effect on pathology or behaviour in APP Tg2576 transgenic mice (Swedish mutant) (90) . S.Pneumoniae displays homology to both the native and mutant forms of the relevant peptide (Table). Borna virus infection resulted in a reduction in beta-amyloid immunoreactivity in the brains of infected Tg2576 transgenic mice (91) . This virus also displays homology to both the native and mutant forms of the peptide (Table).  S.Pneumoniae also expresses proteins containing the VGGVV sequence, as do a large number of other bacteria (not shown), while a homology search for Borna virus proteins containing VGGVV yielded no hits. However, in relation to autoimmunity, it is not the infection itself, but the antibodies generated in response to the infection that could cause the problem. A more suitable test might be repeated challenge with specific antigens in APP transgenic models.  

            Other models capable of producing cerebral beta-amyloid deposition in mice include C.Pneumoniae (92) or HSV-1 infection (11) , the latter also producing hippocampal and entorhinal cortex neuronal loss and memory deficits, perhaps more faithfully reproducing the pathology of Alzheimer’s disease  (13) . Such models may be useful in APP transgenic mice.

           

 

Beta-amyloid and other Vaccines and therapies.

.

            The F,G and I  APP717 mutants all generate peptides homologous to the related Vaccinia and Variola (Smallpox) viruses (Table 4,6) . While vaccination against diphtheria, flu, tetanus and polio have been reported to reduce the risk of late-onset Alzheimer’s disease (see above) there is also a possibility of vaccine cross-reactivity with endogenous peptides such as beta-amyloid. Many of the epitopes formed by these mutant peptides are contained within Vaccinia viral proteins. There is thus a possibility that smallpox vaccination may be a contributory factor in familial Alzheimer’s disease, although this requires characterisation of the epitopes present in the vaccine, which was generated from the virus rather than from peptide components. The vaccinia virus has also been used as a primary vaccination against smallpox (93) following on from Edward Jenner’s pioneering experiments with cowpox over 200 years ago (94) . This is a contentious area, but the possibility that vaccination might trigger nefarious autoantibody generation does need to be addressed, particularly in future studies.

            The potential use of beta-amyloid antibodies is based on their ability to reduce plaque burden and neurite dystrophy in APP transgenic mice (95)

Several studies have demonstrated that beta-amyloid antibodies reduce plaque burden in APP transgenic models and that they can also improve cognitive performance (96) . However amyloid antibodies extracted from the serum of old APP transgenic mice potentiate the toxicity of beta-amyloid and Alzheimer’s disease patients display an enhanced immune response to the peptide (97) . Again in transgenic mice, different immune backgrounds can influence the type of immune responses elicited by beta-amyloid. For example B-and T-cell responses to beta-amyloid can be modified in HLA-DR3, -DR4, 

-DQ6 or  -DQ8 transgenic mice (98) .  HLA-antigen diversity in Man is also likely to determine the outcome of beta-amyloid/antibody interactions.

            The results of this survey suggest that beta-amyloid autoantibodies might cause as well as mitigate against Alzheimer’s disease pathology. Beta-amyloid vaccination in Alzheimer’s disease (against Abeta1-42) has so far not been successful and sadly resulted in meningoencephalitis and the death of a patient (99) . While certain beta-amyloid antibodies may reduce plaque burden, there is an evident risk that they may also trigger an auto-immune response, potentially killing beta-amyloid containing neurones. Catalytic autoantibodies are less able to form stable immune complexes and likely represent the safest way forward in this area (2) . It is intriguing that the beta-amyloid region targeted by catalytic autoantibodies matches peptide sequences of viruses that are constituents of the Mediterranean diet and of cancer-inducing viruses (Epstein-Barr, Hepatitis B, and the papillomavirus) as both cancer and the Mediterranean diet are inversely associated with Alzheimer’s disease risk (see above). Vaccines to the human papillomavirus already exist (47) and could perhaps be considered as a therapeutic or preventive option in Alzheimer’s disease, after due consideration of the epitope matches.

            If beta-amyloid autoantibodies are the culprits, techniques such as immunoadsorption, which has proved to be of benefit in Myasthenia gravis (autoimmunity to acetylcholine receptors (100) or immunosuppressant use might be considered as potential therapeutic options. There is indirect evidence in support of such treatment. Natural immunoadsorbants include silica, which is however toxic, (101) , tryptophan and phenylalanine (102) . Levels of silica in drinking water are inversely related to Alzheimer’s disease risk (103) and serum tryptophan levels are markedly depleted in Alzheimer’s disease patients, a marker of immune activation (104) .Phenylalanine plasma levels are in contrast increased in Alzheimer’s disease (105) . Fish oil (see above) also suppresses T-Lymphocyte activation (106) and statins, which have also been reported to reduce Alzheimer’s disease risk (58) are also immunosuppressant (62) .

 

Heterogeneity in genetic and epidemiological studies

 

            If there is one factor common to polygenic disorder research it is the discordance of genetic and environmental association data in this and other diseases. However, if, as suggested by this survey, there are dozens of potential Alzheimer’s disease triggers, all funnelling towards a common cause, this heterogeneity becomes part of the answer and not part of the problem. Different gene products are related not only to human physiology, but also to pathogen life cycles (e.g. rhinoviruses and lipoprotein receptors, APOE and Herpes Simplex or influenza and complement receptor 1) , a situation that has been discussed in relation to Alzheimer’s disease and Schizophrenia susceptibility genes and pathogens implicated in these disorders (107;108) .  Viruses and bacteria are not uniformly distributed worldwide, nor is antibody seroprevalence, and different environmental risk factors may similarly vary from region to region. The heterogeneity observed in these studies thus has a rational basis, reflecting the heterogeneity of cause, and need not necessarily be considered as a statistical artefact

 

Relevance to other autoimmune and genetic diseases and evolutionary aspects

.

            A homology search against viral proteomes with known autoantigens from multiple sclerosis, myaesthenia gravis, pemphigus vulgaris, systemic lupus erythematosus, and Chronic obstructive pulmonary disease retuned viral matches, which in all cases were relevant to the viruses implicated as risk factors in each disease (Table 8) , also identifying other suspects. Furthermore, in other genetic disorders, Huntingtons’s disease and other polyglutamine repeat disorders (Dentatorubropallidoluysian atrophy, Kennedy disease  and Spinocerebellar ataxias (109;110) ) and  Cystic fibrosis, the mutations created homologues with several  viral or phage proteins. The QQQ polyglutamine triplet is a B-cell epitope according to the BEpiPred server and each successive QQQ addition increases the overall antigenicity of the resulting peptide (not shown). As an example of a risk promoting gene in polygenic disorders, APOE4 also aligns with several relevant viral proteins. Given the capacity of the immune system to generate vast repertoires of antibodies, some of these pathogens will no doubt generate antibodies that also target important human proteins implicated in autoimmune and genetic diseases. The genetic mutations often create physiological problems related to their normal function and the effects of the mutation, but the overall effect of the mutation, particularly in relation to autoimmune-related degeneration, may be compounded by these viral matches.

            Phages and viruses are the simplest form of “life”, as defined by the possession of DNA/RNA and a proteinaceous structure,  and were long ago proposed as the origin of higher cellular organisms (111;112) . There are currently 2463 viral genomes in the NCBI database, probably representing but a small proportion of those existing on the planet. While perhaps responsible for our origin these predecessors may have donated a legacy of human viral-derived proteins that closely match antigenic proteins in the currently existing virome that could be responsible for many human diseases including genetic disorders, autoimmune disorders, polygenic diseases, and those that have so far baffled research, such as  ME (Myalgic encephalomyelitis/chronic fatigue syndrome) and fibromyalgia. This evidently has enormous implications for therapy and prevention, not only of autoimmune disorders, but also of polygenic and human genetic disorders, until now generally regarded as unassailable. Vaccination, using epitopes against the non homologous human protein regions of the phages and viruses could perhaps destroy the pathogen and prevent the associated problems related to autoimmunity.         

 

Summary and conclusions    

 

            Many common viruses, phages, bacteria, fungi, parasites and allergens express proteins with marked homology to antigenic and other regions of the beta-amyloid peptide. Epitope similarity with beta-amyloid is concentrated within these classes and it seems likely that these antigens provide a source of the beta-amyloid autoantibodies found in the ageing population and in Alzheimer’s disease. While some of these antibodies may be benevolent, others may stimulate immune, inflammatory and other defensive measures, including complement mediated cell lysis that could kill the neurones in which the peptide resides. Activation of the immune system is supported by the presence of many immune-related proteins in Alzheimer’s disease amyloid plaques, and by the presence of the complement membrane attack complex in Alzheimer’s disease neurones. Reduced serum tryptophan levels, and an increased immune response to beta-amyloid also suggest immune activation.  Familial Alzheimer’s disease may also have a strong autoimmune component, as the various APP mutants convert the surrounding peptides to matches to commensal bacteria (E.Coli, E.Faecalis and P.Gingivalis) and to viruses with a high seroprevalence (HHV-6, polyoma viruses, influenza and the common cold rhinoviruses). The categorisation of Alzheimer’s disease as an autoimmune disorder explains most of the epidemiological observations in Alzheimer’s disease and the major genes implicated in Alzheimer’s disease are all related to viral life cycles and/or to the complement arm of the immune defence network.    

            Diseases caused by these viruses, fungi or the bacteria infected with the phage/beta-amyloid homologues are very common and often recurrent (e.g. colds, influenza gastroenteritis or food poisoning) as is exposure to certain allergens (e.g. dust mites , cat, cow, horse allergens, pollen and food allergens, insect stings, marine algae etc)   Over time, and with increasing age, the major risk factor in Alzheimer’s disease (113) , antibodies that may also target beta-amyloid are more likely to be produced, gradually increasing the probability of a self-immune attack on neurones containing the beta-amyloid peptide. There may thus be dozens, if not hundreds of triggers promoting Alzheimer’s disease risk, all funnelling towards an autoimmune scenario. If this is the case, then Alzheimer’s disease might be considered as an autoimmune disorder and immunosuppressants or antibody adsorption might have a role to play in its therapy, once diagnosed. C.Neoformans eradication can result in a complete recovery, in very rare cases of diagnosed dementia (28;29) , and Helicobacter elimination has been reported to ameliorate cognitive function in infected Alzheimer’s disease patients (25) . Aggressive targeting of opportunistic pathogens capable of mimicking the beta-amyloid peptide might thus be considered as a therapeutic option. Because so many are homologous to beta-amyloid, such therapy might well have to be tailored to individual pathogens, depending on the species identified by serum assay.

            Vaccination against common diseases has already been shown to reduce the risk of developing Alzheimer’s disease (46) and, in the long term, vaccination against other common viruses and bacteria might also be of benefit, although it is evident that potential vaccine antibody cross-reactivity with beta-amyloid must be a prime concern. One such vaccine may already exist in the form of that for the human papillomavirus.

            .   In summary, the close homology of diverse viral, fungal bacterial and allergenic antigens with beta-amyloid and to peptides generated by APP mutations suggests an autoimmune component to familial and late-onset Alzheimer’s disease, triggered by these antigenic homologues. The autoimmune scenario explains many epidemiological observations and genetic studies also implicate the immune system and viral life-cycles. If autoimmunity is important, vaccination, viral and pathogen elimination and immunosuppressant therapy might be expected to play a role in the prevention and therapy of Alzheimer’s disease and perhaps provide new rationales for developing a cure.  This type of viral matching is also relevant to other autoimmune and genetic disorders and may be a near universal phenomenon reflecting our viral ancestral roots. This generality could open new therapeutic avenues in many human diseases.

 

 

Acknowledgements: Thanks to the numerous authors for reprints, to Oliver Chao and Nasire Mahmudi for finding others, and to Maria Jesus Martin at Uniprot and Tao Tao at NCBI for help with the mysteries of BLAST and Clustal alignment settings.

 
 
 

Table 1: Virus and phage proteins containing the VGGVV sequence, and the diseases they cause. Accession numbers are provided and seroprevalence is recorded for human viruses where available.

 

Virus

Protein VVGGV

Disease

Seroprevalencs

Human Viruses

Dengue virus 1

ACQ44424

Polyprotein

Febrile tropical disease

Endemic in some countries (eg 100% seroprevalence in Jamaica) (114)

Hepatitis C

ACY65348 envelope protein 2 :

 ADG28960 NS4A

ABC58527

NS4B:  ADC54771

Polyprotein

Hepatitis

An estimated 270-300 million people worldwide are infected with hepatitis C

1.8% (USA) (115)

Human adenovirus 8

BAH18864 17.7kDa protein

Keratoconjunctivitis

?

Human herpesvirus 1

P08665

Envelope glycoprotein B:

ABI63489

UL27

Cold sores, mouth, throat, face, eye and CNS infection

68% (USA) (116)

Human herpesvirus 2

NP_044471

uracil-DNA glycosylase:

BAG49514

Glycoprotein B

Anogenital infections

16% in USA adults aged from 14-49: Higher in women (20.9%) and Afro-Americans (39%) (51)

Human herpesvirus 6

AAA43846

Envelope glycoprotein B

 

Approaching 100% (86)

Human herpesvirus 6B

BAA78260

Envelope glycoprotein B

Causes Roseola, a near-universal childhood disease

Approaching 100% (86)

Human immunodeficiency virus

ACQ42512

vif Protein

Acquired immune deficiency syndrome

Rare 0.02% (USA) (117)

Lactate dehydrogenase-elevating virus

YP_001008394

Polyprotein 1ab

Not well characterised

?

Polyomavirus HPyv6 and 7

ADE45477

VP2

Human infection

No data on these strains but for other polyoma viruses can range from 9 to 69% (87)

Yellow fever virus

NP_776003

Polyprotein : NS2A

Yellow Fever

75% Nigeria (118)

Phages infecting human bacteria and diseases associated with the bacteria

Aeromonas phage

 

YP_238875

WAC

Gastroenteritis and wound infections

Enterobacteria phage

NP_037676

tail length tape measure protein

 

Normal gut flora, many of which can cause gastrointestinal problems

Escherichia phage

Chain A, Ibv: YP_002003548

hypothetical protein

Many are harmless but can cause diarrhoea to dysentery

Mycobacterium Phage

ACU41726

GP233

YP_002014682

GP71 YP_655916

YP_655355 GP51 GP78

NP_818073

GP108

Pulmonary disease, Tuberculosis and leprosy

Prochlorococcus phage

 

ACY76180

Hypothetical protein

Marine cyanobacteria

Pseudomonas phage

 

Tail fiber assembly protein

 

Nosocomial hospital infections

Serratia phage KSP20

 

TAILC_BPSK2

Nosocomial hospital infections

Streptomyces phage

 

NP_958289

ORF9

Antibiotic producing bacteria

Vibrio phage

 

AAQ96489

 Hypothetical protein

Gastroenteritis, septicaemia

Other phages

Azospirillum phage

YP_001686888

Hypothetical protein

Nitrogen fixing plant bacterium

Halomonas phage

 

  YP_001686782

hypothetical protein HAPgp46

 

Salt water

Microcystis aeruginosa phage

 

 YP_851126

hypothetical protein MaLMM01_gp112

 

Harmful blue-green algae

Prochlorococcus phage

 

 

ACY76180

 hypothetical protein PSSM2_305

 

Common marine cyanobacteria 

Synechococcus phage

 

 YP_003097380

 tailfiber like protein

  hypothetical protein SRSM4_083

Marine cyanobacteria

Agricultural Viruses

Bovine herpesvirus 5

YP_003662471 Envelope glycoprotein K

 Cattle

Bovine herpesvirus type 2

P12641 Envelope glycoprotein B

 Cattle

Bovine viral diarrhea virus

CAD67689 hypothetical protein

 Cattle

Avian infectious bronchitis virus

ACJ12832 polyprotein 1ab

 Poultry

Infectious bronchitis virus

Replicase polyprotein 1ab: , Ibv Nsp3 Adrp Domain

 Poultry

Equid herpesvirus 1, 4 and 9

YP_002333504

NP_045240

YP_053068 

tegument protein UL37

 Horse

Suid herpesvirus 1

YP_068340.Tegument protein UL37

 Pigs

Swinepox virus

NP_570175 kelch-like protein  

 Pigs

Plant, food and environmental viruses

Anguillid herpesvirus 1

YP_003358210

ORF71

Eel

Viral hemorrhagic septicemia virus

ADB93794 Polymerase: Large protein

Fish

Cherry necrotic rusty mottle mosaic virus

ABZ89196Replication  protein

Cherry

Radish mosaic virus

BAG84603 Polyprotein

Radish

Watermelon mosaic virus

ACF60797 Polyprotein

Watermelon

Ostreid herpesvirus 1

YP_024568ORF23

Oyster

Arabis mosaic virus

BAF35852 Polyprotein: NTB binding domain

Strawberries and raspberries

Viral hemorrhagic septicemia virus

ADB93794Polymerase; Large protein

Fish

Shrimp white spot syndrome virus

NP_477731  wsv209

Shrimp

Antheraea pernyi nucleopolyhedrovirus

ABQ12330  ETM

Environment Insect

Chinese Tuss Moth

Murid herpesvirus 2

NP_064139  pR34

Environment Rodents

Allpahuayo virus

NP_064139 Nucleocapsid protein

Environment Rodents

Helicobasidium mompa endornavirus 1

YP_003280846 Polyprotein

Environment Root rot fungus

Paramecium bursaria Chlorella virus

YP_001498106 and others Hypothetical proteins

Environmental Algae

Archaeal BJ1 virus

YP_919057  hypothetical protein BJ1_gp30

Environmental

West Caucasian bat virus

YP_919057. Glycoprotein G

Environmental Bat

Cyprinid herpesvirus 3

BAF48875 

ORF62

Family pet Goldfish

Caviid herpesvirus 2

BAF48875

GP144

Family pet Guinea Pig

Macropodid herpesvirus 1

AAD11961 Glycoprotein B

Zoo  Marsupial

Macropodid herpesvirus 2

AAD11960.

Glycoprotein B

Zoo  Marsupial

Macacine herpesvirus 1

NP_851887 Glycoprotein B

Zoo Monkey

Cercopithecine herpesvirus 1, 2 and 16

BAC58067 eg

Envelope glycoprotein B

Zoo Monkey

Papiine herpesvirus 2

AAA85650

Envelope glycoprotein B

Zoo Monkey

Chimpanzee alpha-1 herpesvirus

BAE47051 Glycoprotein B

Zoo Monkey

Allergens

Lichwort :Parietaria officinalis

AAB36010

major allergen {N-terminal, band 2}

Non-stinging nettle family growing on rubbish and walls

 

Table 2:

Viral and allergen proteins matching tetrapeptide sequences, or more, within the beta-amyloid peptide (1-42).  Shaded dark grey blocks represent viral matches to pentapeptides, or more, as shown by the numbers in each block. Allergens are boxed in light grey and protein accession numbers are provided. Species with protein epitopes containing these sequences are also illustrated. Short beta-amyloid epitopes (antibodies raised to peptides of 4-6 amino acids) are illustrated by the grey boxes with dashed surrounds. Matches to these short immunogenic peptides are perhaps more likely to cross-react with beta-amyloid.

 

 

Tetrapeptide

Viral and allergen proteins

Species with epitopes containing this sequence

Human /Mouse Epitopes

 

DAEF 

Acc:158998780 Pecan

Acc:18479082Hazelnut 4

 

 

 

Beta amyloid

 

Corylus avellana (Hazel antigen,) Entamoeba histolytica (dysentery), Trypanosoma cruzi

Beta-amyloid

 

 

AEFR

Acc:157418806 Herring worm 4

 

 

 

 

Junin, Machupo  and Vaccinia virus

 

Beta-amyloid

Beta-amyloid

EFRH

Coxsackie Virus B2 Capsid protein VP1; AAD17716

5

Polyprotein Rhinovirus C ABK29455 4

Acc: 7117013 Bumble bee venom 4

AC:A23876 Bahia grass pollen 4

Beta amyloid

 

Beta-amyloid

FRHD

gp35 Vibrio phage KVP40

NP_899628 5

gp037 Rhodococcus phage ReqiPepy6 ADD80928 4

Polyprotein Hepatitis C virus subtype 1b ACJ37243

5

 

 

Streptomyces griseoflavus and pristinaespiralis, Deinococcus radiodurans

Beta-amyloid : Glutamate receptor-interacting protein 1 Homo sapiens

RHDS

Human respiratory syncytial virus CAA24906 4

 

Beta amyloid

Corynebacterium genitalium

Beta-amyloid

 

HDSG

Polymerase European bat lyssavirus 1 ACF37166

Polymerase Duvenhage virus ACF37214

polymerase Lyssavirus Ozernoe ACS70797

Large protein Rabies virus ADD84791 5

38.7KD protein Choristoneura occidentalis (Western Spruce Budworm) granulovirus YP_654475

6

 

 

 

 

 

Human herpesvirus 4

Beta-amyloid

 

DSGY

hypothetical protein P27p15 Enterobacteria phage phiP27

putative helicase NP_543067 Enterococcus phage phiEF24C YP_001504154.

5

Acc: 119633262: American house dust mite 4

 

Haemophilus influenzae Subtype 1H

Monkeypox virus

Tityus serrulatus (Scorpion venom)

Beta-amyloid

 

SGYE

HIV-1 reverse transcriptase ABO63585 4

large protein Rabies virus

ADD8479

5

Acc: 8118428 :

Rice pollen

Acc: 295812 Tomato 4

 

West Nile virus

Beta-amyloid

 

GYEV

putative DNA polymerase Pseudomonas phage LKA1 YP_001522870 4

 

HIV-1 reverse transcriptase AAZ49919

5

 

 

Vaccinia Virus

Beta-amyloid

 

YEVH

 

Polyprotein Potato virus Y:

AAG44632

 Pepper mottle virus PEMV capsid protein

AAA46902

 : Nib-CP polyprotein Amaranthus viridis leaf mottle virus

CAE30467

polyprotein Sunflower chlorotic mottle virus

ACA00155 6

 

 

 

 

-

Beta-amyloid: Integrin Alpha M Mus Musculus

 

EVHH

Polyprotein bovine viral diarrhea virus

AAC06278

5

 

 

AAG4447 Penicillium oxalicum 4

 

 

-

Beta-amyloid

 

VHHQ

 

 

 

 

-

Beta-amyloid

 

HHQK

Human papilloma virus Oncoprotein E6

AAK95780

5

 

Acc: 5777414: Rubber plant

Acc:62530262 Mugwort 4

Acc: 149786149

Pistaccio

4

 

 

-

Beta-amyloid

 

HQKL

 

 

 

 

 

Streptococcus pyogenes; SARS coronavirus

Guanarito virus

Beta-amyloid

 

QKLV

ORF1 Hepatitis E

5

Acc: 119633262 American House dust mite allergen:

Acc: 20385544European House dust mite allergen4

Acc: 8118439 Rice allergen:

Acc: P40918 Davidiella tassiana fungal plant pathogen: Acc: Q92260Heat shock 70 kDa proteinPenicillium citrinum Fungus

Acc: P51528

Eastern yellowjacket venom

Acc: P49369 Common wasp venom

4

Acc: Q6R4B4

Alternaria alternata fungus (causes asthma  4

 

Plasmodium falciparum; Hepatitis E virus,  HIV-1

Beta-amyloid

 

Clostridium botulinum

Hepatitis E virus,

 

KLVF

AAB23464 Soybean allergen

Acc: 170899 Candida boidinii

 

 

 

 

Beta-amyloid : Sus Scrofa: zona pellucida sperm-binding protein 3

 

 

SARS coronavirus, Plasmodium falciparum, Clostridium botulinum, SARS coronavirus, Canine parvovirus

 

LVFF

 

polyprotein Zucchini yellow mosaic virus 6

P27762 common ragweed pollen:

ACA23876 Bahia grass pollen   4        

P30440

Major cat allergen

4

 

 

Chlamydophila pneumoniae,Vaccinia virus

Beta-amyloid

 

VFFA

HSV-3 tegument protein CAI44881 4

Polyprotein Dasheen mosaic virus

4

 

 

gp24 Mycobacterium phage

ACF05027

 

5

 

Major allergen Felis catus

Beta-amyloid

 

FFAE

ORF037 Staphylococcus phage 37 4

 

Fowl Adenovirus D ORF19

AAC71680                unknown fowl adenovirus 8

AAC71680

 

6

 

Bacillus anthracis

 

Mouse Annexin A7

 

FAED

 

Gallid HerpesVirus 2 UL37-like protein

ABF72276

6

Acc: 467660 Davidiella tassiana fungus

Acc: Q9HDT3 Alternaria alternata:

Acc: 14585753

Cochliobolus lunatus

Acc: Q870B9E

Rhodotorula mucilaginosa: AC:1392587 Aspergillus fumigatus

Acc: 13991101 Penicillium citrinum.

 (All Fungi) 4

           

 

polyprotein Kelp fly virus

polyprotein Kelp fly virus

5

 

Acc: P02769

Cow Allergen

Acc: 399672 Horse allergen 4

Vibrio vulnificus

Beta-amyloid

 

AEDV

HSV-1 gB: Adenovirus 52 hexon

HIV-1

: nonstructural protein 1 Influenza A virus 4

Acc:P43213PolCommon Timothy pollen

Acc:P27760

Short ragweed:

Acc:4090265 Kentucky blue grass;

C37396

reed fescue:

Acc:P43216 Velvet grass

Acc:375486372 Candida albicans 4

Acc:1545803 American house dust mite Acc:6492307

Maynes House dust mite Acc:20385544

European house dust mite

 

 

HSV-1, Hepatitis C; Mycobacterium tuberculosis, Pollen antigen Phleum pratense, Plasmodium vivax, Schistosoma mansoni

Beta-amyloid :H.Sapiens 60 kDa heat shock protein, mitochondrial precursor

 

 

EDVG

Polyprotein precursor Rubella virus

Envelope; glycoprotein G Human herpesvirus 2 4

putative receptor binding protein Lactococcus phage HD3

AAT81524

6

 

 

Acc:4826572  Common timothy 4

 

ADH04370             envelope glycoprotein Human immunodeficiencyvirus 2 6

 

 

 

HSV-2, Rubella virus

Beta-amyloid

 

DVGS

Polyprotein Human rhinovirus C 4.

 

 

 

Mycobacterium tuberculosis

Beta-amyloid

 

VGSN

HIV-1 env

ACB36783 5

BAH09387Arthroderma vanbreuseghemii

(Rabbit dermatophyte)

Gb:121584258

 Penicillium citrinum 4

 

Hepatitis B virus, Yellow fever virus, Candida albicans, Tacaribe virus

Homo sapiens amylin; Beta-amyloid

islet amyloid polypeptide precursor Mus musculus

 

GSNK

Hypothetical phage protein Campylobacter phage CP220

6

 

fiber protein Human adenovirus D

5

Acc: P00785

Actinidain Chinese fruit:

Acc: 166317 Delicious macaque peach 4

Acc: 51093373 Fire ant venom 4

 

Plasmodium berghei

Beta-amyloid: Homo sapiens, Immunoglobulin M

 

SNKG

Hemagglutinin Influenza A virus A/mallard/Ohio

ABJ16576

6

 

 

 

polyprotein Large-leaved lupine mosaic virus 5

Acc: P25780 Europeaun house dust mite;

Acc: P25780 Maynes house dust mite: 6

Acc: 167782086 Common Wasp venom Acc: 2038554 European House dust mite

4

Bovine respiratory syncytial virus; Spirosoma linguale

Beta-amyloid

 

Acc: 166531 Aspergillus oryzae fungus 5

 

NKGA

Acc: 11963326 American House dust mite

5

 

 

Human respiratory syncytial virus, Clostridium botulinum

Beta-amyloid : Homo Spiens Collagen: C.Elegans protein

 

Acc: 47606004 Japanese Cypress

Acc:O64943

Juniper 4

KGAI

HIV-1 envelope glycoprotein ACX43323

6

 

Acc: 2342526

IgE autoantigen Homo sapiens

Acc:2723284

SART-1 autoantigen  Homo sapiens 4

Acc: 169973

Soybean allergen 4

 

Plasmodium falciparum,Bacillus anthracis

Beta-amyloid

 

GAII

Mumps Virus Fusion protein AAK83222 

HSV-6 H86

AAC40335

Tail length tape measure-related protein Salmonella phage SETP3

YP_001110853

:4

nonstructural protein 1 Influenza A virus (swine)

ACV93293

5

 

HIV-1 env

HM001426 6

 

Acc: Q9SQI9  Peanut allergen

4

 

crispr-associated protein Cas5, hmari subtype Clostridium phage

ZP_04863779

 

6

Chlamydia trachomatis

 

Beta-amyloid , H.Sapiens. dihydrolipoamide S-acetyltransferase

 

AIIG

ACC:O04725

Couch grass pollen

ACC:Q9M7M8 Rubber plant pollen

ACC:Q9XG85

Stickyweed pollen

Q9XF37

Celery Pollen

ACC: 16555785 Pepper plant

ACC: 16555787 Tomato

ACC: 27528312

Peach

ACC: 57021110 Cantaloupe melon ACC: 12659206 hazelnut

ACC:O65810Soybean  ACC: Q9XF41 Common Apple

ACC: 15809696

Lychee

 

 

 

ACC: 18652049 Wild carrot

ACC: 2317674

Buckwheat 4

Human herpesvirus 5,  Vaccinia virus, Dengue virus 2, Bovine viral diarrhoea virus 1, Pseudomonas aeruginosa

Sabia virus, Vaccinia virus, Coxiella burnetii, Brucella melitensis biovar Abortus

Beta-amyloid :

 

IIGL

Conserved hypothetical protein Pseudomonas phage D3

AAF80834

putative protein Lactobacillus prophage Lj965

AAR27468

4

 

4

 

Acc: P51528 Eastern yellow jacket venom

Acc: P53357 Bald-faced hornet venomAcc: P49369Common Wasp venom Acc: 45510887 Paper wasp venom

Acc:2231297

Cockroach allergen 4

Polyprotein St Louis encephalitis

polymerase

ABN11819

Newcastle disease virus

ADF59230

4

 

 

RNA polymerase Oropouche virus

NP_982304

structural polyprotein precursor Kyzylagach virus

AAO33327

polyprotein Porcine teschovirus

AAK12398

neuraminidase Influenza virus

CAZ64818

Polyprotein Sindbis virus

BAH70330

5

 

Beta-amyloid

 

IGLM

polyprotein Hepatitis C virus

BAH70330

 

HIV-1 env 5

 

West Nile virus polyprotein

ACX45222 4

 

Capsid proteinAndean potato mottle virus

AAA42421

6

 

Acc: 5815436 American House dust mite 4

 

 

 

Escherichia coli, Human adenovirus 5

Beta-amyloid

 

GLMV

putative DNA polymerase Burkholderia phage BcepC6B

AAT38391 5

 

 

Potato virus Y, Brucella abortus, Mycobacterium  tuberculosis, Yersinia pseudotuberculosis

Beta-amyloid

 

LMVG

Hypothetical protein Streptococcus phage PH10

CAY56537

 

 5

Polyprotein Yellow fever virus

AAB01971

6

 

hypothetical protein Bovine viral diarrhea virus strain 3887 CAD67689

7

 

 

West Nile virus

Beta-amyloid

 

MVGG

Hepatitis C Ns4b

ABC58497

HIV-1 gag

GQ371529

 

 

replicase Cherry necrotic rusty mottle virus

ABZ89196

6

 

 

AF177380_1 Couch grass

BAA07773| Rice allergen

Acc:3749962

Peanut allergen 4

 

 

 

 

 

Salmonella enterica

Beta-amyloid

Beta amyloid

 

VGGV

69 Viruses and phages See Table 1 5

Acc: 10944737

Hazel pollen: AAB36010: Stickyweed pollen

Acc: P25985 Kidney bean:

Acc: Q2VU97

Mung Bean

Acc: 21044 Common Bean: Acc: 1398916

Acc: 963013 Aspergillus fumigatus 4

Acc: P49275Mite allergen Der f 3 American house dust mite 4

 

West Nile virus, Hepatitis C virus, Porphyromonas gingivalis

Beta amyloid

GGVV

Polyprotein Bovine viral diarrhea virus 2

AAA82981 

6

Poliovirus 1 Polyprotein

AAQ03174 4

 

AAB36010 Stickyweed

Acc: P85894

Black mulberry

Acc:7803879 Malassezia sympodialis Yeast: Acc: 3754863729 Candida albicans

Acc: 6492307 precursor Maynes House dust mite

Acc:20385544 European House dust mite

4

Corynebacterium diphtheriae, Guanarito virus, Hepatitis C, Whitewater Arroyo virus

 

Beta-amyloid :Bos Taurus: retinol binding protein 3, interstitial precursor

Beta amyloid

GVVI

Acc:14161637

Pineapple

Acc: Q9XF41

Apple

Acc: P16348

Potato  4

Acc: Q5EF31

Crocus pollen

Acc: 20736624 Common wheat

Acc: 2317674 Buckwheat

Acc: O22655

Maize

Acc: P52184 Barley 4

 

 

HSV-1 UL45

NP_044647 4

 

Schistosoma mansoni, Mycobacterium tuberculosis, Streptococcus mutans

Human ACAN protein

 

Beta-amyloid ;

Beta-amyloid

VVIA

Acc: 51316214 London Plane pollen

 Acc: O04403 Stickyweed pollen

Acc: 21751

Wheat

Acc:A0AT29Lentil

4

 

Acc: 88657350 German cockroach

Acc: Q8T5G9 Archaeopotamobius sibiriensis (Crustacean)

Acc:413817

Malassezia sympodialis (Yast)

4

 

 

 

 

 

Francisella tularensis, Mycobacterium avium

Yellow fever virus,  Vaccinia virus, Streptococcus sobrinus, Human parainfluenza virus 2

 

 

 

 

 

Table 3:  Beta-amyloid homologous regions for proteins from Borrelia Burgdorferri, Chlamydia Pneumoniae, Helicobacter pylori, Porphyromonas Gingivalis and Streptococcus Mutans. Protein accession numbers are provided and proteins with matches to pentapeptides or more are boxed in grey. The number of matching amino acids is shown in each box.

 

Tetrapeptide

Bacterial and Fungal proteins

DAEF

 

 

 

 

 

AEFR

C.Neoformans

XP_568788     nucleoporin nup189

8

 

 

 

 

EFRH

 

 

 

FRHD

 

 

 

RHDS

Porphyromonas gingivalis YP_001930121       nicotinate phosphoribosyltransferase

5

 

 

HDSG

 

 

 

DSGY

 

 

 

 

 

SGYE

 

 

 

 

GYEV

P. Gingivalis AAQ66366      GDP-mannose 4,6-dehydratase

5

 

 

 

YEVH

 

 

 

EVHH

 

 

 

 

 

VHHQ

 

 

 

 

 

HHQK

C.Neoformans

EAL22689       CNBB1380

CNBB1380 5

Streptococcus mutans

NP_720522 UA159

5

 

 

 

 

HQKL

Borrelia Burgdorferri YP_002474437            4

 

 

QKLV

Streptococcus mutans

YP_003485284       putative deacetylase NN2025 5

P. Gingivalis

NP_905110     4

Helicobacter pylori YP_003058029            5

 

KLVF

 

C.Pneumoniae NP_225149     4

Helicobacter pylori

ABF84522

5

LVFF

 

P. Gingivalis

BAA35086 4

 

 

VFFA

 

 

 

 

 

 

 

 

 

 

 

FFAE

P. Gingivalis

YP_001929160 alpha-amylase

5

 

 

Borrelia Burgdorferri YP_002375334           

 

 

FAED

C.Pneumoniae ACZ32801 ACZ32801                        5

Borrelia Burgdorferri

ZP_03087390  4

 

 

AEDV

 

 

 

 

EDVG

 

 

Borrelia Burgdorferri YP_002775754       4

 

 

DVGS

Borrelia Burgdorferri ZP_03796379 

5

 

 

 

 

VGSN

 

 

 

 

GSNK

 

 

Borrelia Burgdorferri AAC69850      4

 

 

SNKG

 

C.Neoformans

AAW43455

5

Borrelia Burgdorferri YP_002640982            4

 

 

NKGA

C.Neoformans

AAW46377     5

 

 

ZP_03796084DNA Borrelia burgdorferi 2 5  

KGAI

NP_223696            Helicobacter pylori

6

ZP_03796006  Borrelia burgdorferi

5

Helicobacter pylori Q9ZKF8

6

GAII

 

 

AIIG

Streptococcus mutans

BAH87814             hypothetical protein NN2025 5

 

 

IIGL

 

NP_722409

Streptococcus mutans UA159

5

 

 

 

IGLM

C.Neoformans

AAW43628     7

 

 

 

 

GLMV

 

 

 

 

LMVG

 

 

Helicobacter pylori ZP_03243748

5 Borrelia Burgdorferri EEG98688              

5

 

MVGG

 

C.Pneumoniae ACZ32927     

6

 

P. Gingivalis

BAG34216     

5

VGGV

C.Neoformans

EAL22148              CNBC2860

AAW47124           CNN01610

AAW42376          

5

Streptococcus mutans  5

YP_003484924      

P. Gingivalis

AAQ66697     

5

 

GGVV

Helicobacter pylori NP_222802

5

GVVI

 

 

 

 

VVIA

 

 

 

 

 

 


Table 4: The effects of the APP717 mutations (in Red) on homology to viral proteins. Protein accession numbers are provided  and amino acid matches are indicated by the asterisks or by the red letter of the mutant amino acid. Species with proteins containing epitopes matching those of the peptide amino acids are also shown (Marked by E). Phages infecting commensal bacteria and common viruses (eg Rhinoviruses and influenza) are highlighted in bold.

 

Native
I
A
T
V
I
V 
I
T
L
V

Schistosoma japonicum

Bovine papillomavirus - 4

Protein tyrosine phosphatase receptor Homo sapiens
 
 
Epi
E
E
E
 
 
 
 

Vaccinia virus: Nicotinic receptor Homo sapiens

 
 
 
Epi
E
E
E
 
 
 

Entamoeba histolytica

Lymphocytic Choriomeningitis virus

Dengue virus 2

Nicotinic receptor Homo sapiens

 
 
 
 
Epi
E
E
E
 
 
Bacillus Phage NP_046589
Rabies virus ACN38519
Salmonella Phage YP_001742070
Sendai Virus BAC79139
*
*
*
*
*
 
 
 
 
 
Aeromonas Phage YP_238915
Enterobacteria phage AC14704
Human Coronavirus 229E CAA49377
Mossman Virus NP_958055
Pseudomonas phage YP_418190
SARS Coronavirus ACZ71766
 
 
*
*
*
*
*
 
 
 
Staphylococcus phage 

YP_024500

 
 
 
*
*
 
*
*
*
*
Aeromonas phage NP_932517, 

Acanthamoeba polyphaga mimivirus

AAV50741

Flavobacterium Phage YP_112527
Mycobacterium Phage YP_002242149
Salmonella phages: Pseudocowpox ADC53802
Uncultured Phage 

ADF97555 Paris Polyvirus X ABF74755

 
*
*
*
*
*
 
 
 
 
Lactococcus Phage P_002875673
Pseudomonas Phage YP_003422512
Ralstonia Phage YP_001165297
Newcastle Disease virus ACZ72939
 
 
 
 
*
*
*
*
*
 
Human herpesvirus 5 (Cytomegalovirus) AAS48926
 
 
 
 
*
*
*
*
*
 
 
SARS coronavirus AAY60778
Burkholderia phage YP_001111213 
Enterobacteria phageYP_001837048
Human rotavirus A BAF95721
Human parainfluenza virus ACZ95446
Human adenovirus 1 AP_000521
Lactate dehydrogenase-elevating virus NP_042576    
 
 
 
 
 
*
*
*
*
*
Vaccinia virus
 
 
Epi
E
E
F 
 
 
 
 
Vaccinia virus
 
 
 
Epi
E
F
E
E
 
 
Vaccinia virus Plasmodium Falciparum
 
 
 
 
Epi
F
E
E
 
 
Apis Mellifera
 
 
 
 
 
F
Epi
E
E
 
Human Herpes Virus 2 AAU93410
 
 
*
*
*
F
*
*
 
 

Ralstonia Phage YP_001949949

Streptococcus PhageCAA87730

 
*
*
*
*
F
 
 
 
 
Bacillus phage NP_046680
 
 
*
*
*
F
*
 
 
 

Human papilloma virus BAC79139

 
 
 
 
*
F
*
*
*
 

Human herpesvirus 3 (Varicella Zoster) ACL67882

Human herpesvirus 8 AAW31674

Verbena virus Y YP_001936181
Vaccinia virus  CAM58311              
Variola virus ABF23093 Mycobacteriophage ADB93732
Enterobacteria phage NP_861932
Bacteriophage phi-105 BAA36658
 
 
 
 
 
F
*
*
*
*
Bacillus phage SPBc2 NP_046680
 
 
*
*
*
F
*
 
 
 
Streptococcus phage PH10 YP_002925182
Enterococcus Phage YP_003358819
Feldmannia irregularis virus AAR26941
Staphylococcus prophage NP_061652 
Human Papilloma virus Type 116 

YP_003084352 and 103 YP_656498

 
 
 
 
*
F
*
*
*
 
Verbena Virus Y YP_001936181
 
 
 
*
 
F
*
*
*
*
SARS coronavirus
 
 
 
Epi
E
G
E
 
 
 

C.Tetani

Human metapneumovirus

Human papillomavirus – 1
 
 
 
 
Epi
G
E
E
 
 

Deerpox virus,Guanarito virus, Hepatitis A virus, Human herpesvirus 5

Human T-cell lymphotrophic virus type 1

Junin virus, Lymphocytic choriomeningitis virus

Mycobacterium tuberculosis, SARS coronavirus

Vaccinia virus WR, Vibrio sp.

 
 
 
 
 
G
Epi
E
E
 
Vibrio Phage NP_899405
 
 
*
*
*
G
*
*
 
 
Puumala virus ACJ22524
 
 
 
 
*
*
G
*
*
*
 
BK Polyomavirus  ADA67892
 
 
 
*
*
G
*
*
 
 
Bacillus phage SPO1 YP_002300316
Lymphocyti choriomeningitis virus ABI96825
Xanthomonas phage YP_001469625
 
 
 
 
 
G
*
*
*
*
Bacillus phage G 
 
*
*
*
*
G
*
 
 
 

Staphylococcus prophage NP_061629

JC polyomavirus BAB93084
 
 
 
 
*
G
*
*
*
 
Highlands J virus ACZ34298
JC Polyoma virus BAC66416
 
 
*
*
*
G
*
 
 
 
Amapari virus YP_001649216
Dandenong virus ABY20732,
Guanarito virus AAP44540
Human T-lymphotropic virus AAT38829
Junin virus AAT40446
Latino virus YP_001936026

Lujo virus YP_002929493

Lymphocytic choriomeningitis virus ABB88931

Oliveros virus YP_001649214
Parana virus YP_001936028

Pirital virus AAP44541

Vaccinia Virus ABZ80096

Variola virus ABF26311

 
 
 
 
 
G
*
*
*
*
Aeromonas phage NP_944088
Bacillus phage SPOI YP_002300316
Burkholderia phage  NP_944301
Iodobacteriophage YP_002128470
Mycobacterium Phage YP_001994770
Vibrio Phage AAN74000
Xanthomonas phage  YP_001469625
 
 
 
 
 
G
*
*
*
*
Lactobacillus phage ADA79910
BK polyomavirus ADA67892
Mycobacterium phage ACU41960
 
 
 
*
*
G
*
*
 
 
Human herpesvirus 6 AAA16727
Human herpesvirus 6B BAA78241                   
Enterobacteria phage RB69 NP_861857
 
 
*
*
*
G
*
 
 
 

Dengue virus 3 HSP60 Homo

Myelin P2 Homo
 
 
Epi
E
E
I
 
 
 
 

SARS Corona virus

Vaccinia virus

 
 
 
Epi
E
I
E
 
 
 

Vaccinia virus WR

Plasmodium falciparum

Lymphocytic choriomeningitis virus

Nicotinic receptor Homo sapiens

 
 
 
 
Epi
I
E
E
 
 
Rhinovirus 50 ACK37391 and >30 other Rhinovirus strains
*
 
 
*
*
I
 
*
*
*

Rhino virus 38 ABF51189

Virus PK224 ADF80719
Aeromonas phage NP_943894
Enterobacteria phage SP  ACY07251
Enterobacteria phage F1 NP_695026 (and others)
Listeria phage YP_002261439
Acanthamoeba polyphagamimivirus YP_001427182

Human herpesvirus 4 YP_401711

Human herpesvirus 5 ACS91947

Aeromonas phage NP_943894

Lymphocystis disease virus NP_078753

SARS coronavirus AAU93319
 
 
*
*
*
I
*
 
 
 
Vaccinia Virus NP_048189
 
 
 
*
*
I
*
*
*
*

Staphylococcus phageYP_238539

Vibrio Phage NP_899546

 
*
*
*
*
I
*
 
 
 

Emiliania huxleyivirus CAZ69528

Enterobacteria Phage ACT66763

Human parainfluenza virus 1 CAA26576
 
*
*
*
*
I
 
 
 
 
Salmonella phage YP_003090232
 
 
 
*
*
I
*
*
*
 

Lactobacillus Phage YP_002790822

Norovirus ADE28700(Numerous strains) 

Norwalk-like virus Epiphyas postvittana NPV

BAF38399

 
 
 
*
*
I
*
*
 
 
Escherichia Phage YP_002003667
Bacillus phage S NP_690718
Mumps Virus AAD56373
GB virus A NP_045010
 
 
 
 
*
I
*
*
*
 

Staphylococcus phage phi YP_002332525

Enterobacteria phage TLS YP_001285537

Ectromelia virus NP_671600

Infectious spleen and kidney necrosis virus NP_612246.

Vaccinia virus ABD52564

Variola Virus CAA53837

Variola Minor Virus CAB54683

 
 
 
 
 
I
*
*
*
*

Melanoma antigen Homo HSV-8 Gb Gb like Homo sapiens

 
 
Epi
E
E
L
 
 
 
 

GAD2 Homo sapiens

 
 
 
Epi
E
L
E
 
 
 

Porcine circovirus

West Nile virus

Nicotinic receptor Homo

 
 
 
 
Epi
L
E
E
 
 

Bacillus Phage NP_690718

Mycobacterium Phage YP_002224980

Pseudomonas phage F116

YP_164316 Influenza B virus (Several strains) Rhodococcus phage ADD81097

 
*
*
*
*
L
 
 
 
 
Influenza A ABO32793
 
 
 
 
*
*
L
*
*
 
*
Dugbe virus NP_690576
Feldmania species virus ACH46782
Hepatitis C virus subtype2a:  AAF25612
Hepatitis C virus (isolate JFH-1)

BAB32872 Aeromonas Phage YP_656454 Staphylococcus phage 29NP YP_240601

Enterobacteria phage RB69

NP_861733

 
 
 
 
*
L
*
*
*
 
Natrialba phage PhiCh1 

NP_666010

 
 
 
*
*
L
*
*
*
 
Hepatitis C ACX44366
Enterococcus phage  YP_001504324
Pseudomonas phage 

YP_001956942

Streptomyces phage NP_813724
 
 
 
*
*
L
*
*
 
 
Enterobacteria phage YP_277477
Lactobacillus phage YP_002117687
Lactococcus phage YP_762602
Staphylococcus phage SAP-2: YP_001491531
Human herpesvirus 4 type 2 YP_001129444
Human herpesvirus 5 ABV71532
Lymphocystis disease virus 1 Mammalian orthoreovirus 

NP_694609

NP_078757Pseudomonas phage 

YP_418089. Staphylococcus phage 85

YP_239732 Human papillomavirus ACS72929

 
 
 
 
 
L
*
*
*
*
Influenza A virus (Queensland ABO32793
Hepatitis C ACX44366 
Enterococcus phage YP_001504324
 
 
 
*
*
L
*
*
 
 
Amsacta moorei entomopoxvirus   'L'
Influenza Virus B (Russia ABQ81845)  (Singapore ABL77016) and others (Connecticut, Memphis, Texas, Vienna, Romania)

Streptococcus pyogenes phage NP_795674

 
 
*
*
*
L
*
 
 
 

               

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 5 The effects of the APP717 mutations on homology to bacterial proteins. Protein accession numbers are provided  and amino acid matches are indicated by the asterisks or by the red letter of the mutant amino acid. Commensal or common soil species are highlighted in bold.

 

Native 180  protein Hits
I
A
T
V
I
V 
I
T
L
V
Ricketsia canadensis A8EYN4
*
*
*
*
*
V
*
*
 
 
Aliivibrio salmonicida B6EPV1
Bacillus coagulans C1PC89
Rhodococcus Q0S6X2
Vibrio Metshnikovii C9P7P7
*
*
*
*
*
V
*
 
 
 
Chlorobium ferrooxidans Q0YSY2
Hoeflea phototrophica A9CXL6
Rickettsia canadensis A8EYN4 (Plants)
Silicibacter pomeroyi Q5LMG7
 
*
*
*
*
V
*
*
 
 
Ralstonia Eutropha Q472E0 (infects plants)
Ralstonia Picketii C6BIS4
Ralstonia solanasereum B5SKC7
Staphylococcus warneri C4W9N9
 
 
*
*
*
V
*
*
*
*
Acinetobacter baumannii A3M8V0
bacterium Ellin514 B9XI38
Carboxydibrachium pacificum B7RAI3
Clostridium asparagiforme C0CUU7
Erwinia tasmaniensis B2VL62
Lactobacillus Brevis Q03NB9
Lactobacillus crispatus D4FF71
Oxalobacter formigenes C3XCI5
Ralstonia solanacereum Q8XYV2:
Ryzobium
Salmonella enterica B5QA19
Salmonella heidelberg B5P6H1
Salmonella typhimurium A9N7S6
Thermoanaerobacter brockii C5UE75
Thermoanaerobacter congensis Q8R7X3
Thermoanaerobacter ethanolicus C7IUT0 
Thermoanaerobacter pseudethanolicus B0KCL9
Thermoanaerobacter mathranii C6Q925
Vibrio fischeri B5EV74
 
 
*
*
*
V
*
*
*
 
Carboxydibrachium pacificum
Clostridium asparagiforme C0CUU7
Clostridium bartlettii B0A6Z5
Clostridium thermocellum A3DFT3
Geobacillus sp. D3EBU3
Halothermothrix oreni B8CZE2
Maricaulis maris Q0AK61
Oligotropha carboxidovorans :B6J9Z4
Ralstonia pickettii B2UHX3
Sinorhizobium medicae A6U9B8
Tsukamurella paurometabola C2AKX9
Yersiniarohdei C4UTM6
Yersiniamollaretii C4SBZ5  
 
 
 
*
*
V
*
*
*
*
Mutant F 859 protein hits 
I
A
T
V
I
F 
I
T
L
V
Aerococcus viridans D4YI11
Brachyspira hyodysenteriae C0QX46
Brevibacillus brevis C0ZA23
Clostridium butyric C4IJA0
Clostridium thermocellum D1NR57
Lactobacillus helveticus C9M4P6
Lactobacillus sakei Q38YE0
Oceanicola granulosus Q2CH54
Rhodobacterales bacterium A3VMF7
Vibrio fischerii B5FCH7
*
*
*
*
*
F
*
 
 
 
Chloroherpetonia thalassium B3QTP3
Enterococcus faecalis Q838I9 (many strains)
Bacteroides vulgatus D4V0E1
 
*
*
*
*
F
*
*
 
 
Vibrio Fischerii Q5E6H3
*
*
*
*
*
F
*
 
 
 
Blautia Hansenii C9L542
Jannaschia sp Q28MI1
Providencia rettgeri D4BTW4
Providencia rustigianii D1NYV5
Rhodobacter sphaeroides Q3IZP4
Yersiniaintermedia C4T272
 
 
*
*
*
F
*
*
*
 
Enterobacter cloacae D5CJ25
Idiomarina loihiensis Q5QU47
Proteus mirabilis C2LG18
Proteus penneri C0B3I7
Providencia alcalifaciens B6XHS9
Providencia stuartii B2Q1T7
Vibrio Furnissii C9PCZ1
 
 
 
*
*
F
*
*
*
*
Mutant G 433 protein Hits
I
A
T
V
I
G 
I
T
L
V
Psychrobacter arcticus Q4FTU9
*
*
*
*
*
G
*
*
*
 
Psychrobacter arcticus Q4FTU9
Streptosporangium roseum D2AZ15
 
*
*
*
*
G
*
*
*
 
Azorhizobium caulinodans A8HZ46
Bacillus mycoides C3AFH5
Catonella Morbia C4FVR1
Desulfuromonas acetoxidans Q1K1U7
Desulfovibrio Sp D2L952 
Desulfovibrio magneticus C4XPD3
Dialister invisus C9LN97
Fusobacterium Varium C6JJE4
Granulibacter bethesdensis Q0BPF8
Hydrogenivirga sp A8V376
Legionella longbeachae D3HQH8
Leuconostoc citreum B1MYU7
Marinobacter aquaeolei A1U1N5
marine gamma proteobacterium A0Z7W7
Methylophaga thiooxidans C0N9Z9
Microcystis aeruginosa B0JM06
Nitrosomonas europaea Q82TG1
Photorhabdus asymbiotica C7BLV9
Vibrio alginolyticus D0X1F5
Vibrio harveyi A7MSV9
Yersinia pseudotuberculosis B7UF92
*
*
*
*
*
G
*
 
 
 
Alcanivorax borkumensis Q0VS59
Bacillus cereus C2Y6K4 (Endemic soil)
Bacillus selenitireducens A8VSL6
Bacillus thuringiensis :C3IF91
Bacillus thuringiensis serovar israelensis Q3EPC6
Colwellia psychrerythraea Q482L7
Cyanothece sp. B1WRV0
Desulfococcus oleovorans Y1531
Dickeya dadantii D2BW75
Grimontia hollisae D0I6P8
Marine algicola DG893
Marinobacter aquaeolei A1U1P8
Natranaerobius thermophilus B2A0H4
Photobacterium angustum Q1ZQS6
Photobacterium profundum Q1Z1I8
Prevotella timonensis D1W1B7
Tolumonas auensis C4LCT3
 
*
*
*
*
G
*
*
 
 
Bacillus licheniformis D2AZ15
Blastopirellula MarinaA3ZUC0
Brevibacillus Brevis C0Z7B6
Clostridium phytofermentans A9KJY1
Porphyromonas gingivalis Q7MVP9
Stenotrophomonas maltophilia B4SHS1
Verrucomicrobiae Bacterium B5JCZ1
 
 
*
*
*
G
*
*
*
 
Acidovorax avenae D1STI2
Acidovorax ebreus B9MID3
Aeromonas hydrophila subsp. A0KHV9
Anaeromyxobacter sp. A7HEH4
Azorhizobium caulinodans A8IHP8
Azospirillum sp :D3P7H8
Bradyrhizobium sp A5EP47
Clostridium bolteae A8S3D7
Clostridium perfringens Q8XMX7
Dichelobacter nodosus A5EXF8
Gemellahaemolysans C5NVY9
Legionella longbeachae D3HN24
Leifsonia xyli Q6AED0
Methylibium petroleiphilum A2SD15
Methylobacterium extorquens C7C7Z2
Methylococcus capsulatus Q608X6
Mycoplasma penetrans Q8EUZ6
Myxococcus xanthus Q1DG48
Nakamurella multipartita C8X6U6
Pantoea ananatis :D4GKU3
Photobacterium profundum Q6LPG3
Polaromonas naphthalenivorans A1VT83
Ralstonia solanacearum A3RYP0
Rhodopseudomonas palustris Q6N682
leguminosarum bv. Trifolii C6AXC8
Rhizobium etli B3PP68
Rhizobium leguminosarum bv. Viciae Q1MBB9 
Rhizobium meliloti Q92T03
Salinispora arenicola A8M7N9
Shewanella putrefaciens A2V1T8
Sinorhizobium medicae A6UEY9
Stenotrophomonas sp. B8KYQ9
Stenotrophomonas maltophilia B4SHS1
Syntrophobacter fumaroxidans A0LQ89
Thermosynechococcus elongatus Q8DHF1
Thermosipho melanesiensis A6LLD4
Thermotoga maritima Q9WYD7
 
 
 
*
*
G
*
*
*
*
Mutant I 158 Protein  Hits
I
A
T
V
I
I 
I
T
L
V

Citrobacter oseri A8AEH8

Citrobacter rodentium D2TQJ9

Clostridium phytofermentansA9KJW1

Desulfobacterium autotrophicum C0QE66

Enterobacter sp A4WC96

Escherichia coli Q8FG29 (many strains)

Escherichia ferguson B7LUH8

Parachlamydia acanthamoebae D1R803

Shigella boydii Q323G5

Shigella dysenteriae B3WWP7

Shigella flexneri Q83R02

Veillonella dispar C4FS24
Yersinia intermedia C4T4Q3
*
*
*
*
*
I
*
 
 
 
Bacillus cereus A7GLY6
Clostridium Humboltae A8RT62
Escherichia coli Q8X7P3
Grimontia hollisae D0I556
Haemophilus parasuis B8F464
Porphyromonas gingivalis B2RJP3
Staphylococcus aureus Q99RA3 Many strains
Xenorhabdus bovienii D3UZ08
*
*
*
*
*
I
 
 
 
 
Lactobacillus brevis Q03NB9
Lactobacillus iners C8PC46
Vibrio metschnikovii C9P8Z2
 
*
*
*
*
I
*
*
*
 
Clostridium perfringens Q8XLI1
Leptospira biflexa B0SNI9
Pedobacter heparinus C6Y2P1
Sphingobacterium spiritivorum C5PSB0
 
*
*
*
*
I
*
*
 
 
Erwinia amylovora D4HU72
Erwinia pyrifoliae D2TBW3
Listeria innocua
Phytoplasma australiense B1V943
 
 
*
*
*
I
*
*
*
 
Bacteroides sp D0TSW3
Bacteroides ovatus A7M5Q2_
Borrelia garinii B7XSM5
Clostridium difficile Q186M9
Clostridium cellulolyticum :B8I278
Corynebacterium urealyticum B1VG78
Pasteurella dagmatis C9PSK3
Proteus mirabilis C2LEY0_
Streptobacillus moniliformis D1AXI5
 
 
 
*
*
I
*
*
*
*
Mutant L 198 Protein  Hits
I
A
T
V
I
L 
I
T
L
V
Acidobactium Q1IJL1
Aggregatibacter actinomycetemcomitans D4ED73
Aggregati bacteria aphrophilus C6AKL6
Abiotrophia defectiva C4G6M0
Azorhizobium Caulinodans A8HQR6
Bacillus megaterium D5DSJ5
Bacillus pumilus B4ADS6
Bdellovibrio bacteriovorus Q6MRD1
Caulobacter crescentus B8H097
Clostridiales bacterium C5EIM1
Clostridium butyricum C4ICE7
Clostridium methylpentosum C0ECW3
Chlamydophila abortus Q5L6C5
Coprococcus Comes C0BFC3
Doreaformici generans B0G8H5
Eikenella Corrodens C0DY03
Mycobacterium sp Q1BC56
Roseobacterium denitrificans Q162L0
Ruminococcus obeum D4LS87
*
*
*
*
*
L
*
 
 
 
Carnobacterium sp A8UAH5
Mycobacterium abscessus B1MP36
Mycobacterium chelonae A5A9P9
 
 
*
*
*
L
*
*
*
*
Bacilluscereus lus Rock3-44 C3AYE2
Bacillus thuringiensis Q3EUN8_
 
*
*
*
*
L
*
*
*
 
Bacillus mycoides C3AYE2
Bacillus pseudomycoides C3BEV6
Gramella forsetii A0LYP6
Lyngbya sp A0YPN4
Lysinibacillus sphaericus B1HWG7
 
 
*
*
*
L
*
*
*
 
Butyrate-producing bacterium D4MSZ1
Citreicella Sp. D0D4G6
Clostridium sp. D4CDQ6
Escherichia coli B5AXC7
Leifsonia xyli subsp.xyli Q6AFD7
Mycoplasma Pulmonis MYPU_0850
Neptuniibacter caesariensis :Q2BPQ0
Rhodopseudomonas palustris Q21C19_
Ruminococcus torques A5KJD0
Staphylococcus hominis C2LWL2
Veillonella dispar C4FNF7
Veillonella parvula D1BQP4
Yersiniarohdei C4UUS1
Yersinia frederiksenii C4SLT3
 
 
 
*
*
L
*
*
*
*

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


Table 6 The effects of the Swedish APP mutation on homology to viral proteins. Protein accession numbers are provided  and amino acid matches are indicated by the asterisks or by the red letter of the mutant amino acid. Species with proteins containing epitopes matching those of the peptde amino acids are also shown (Marked by E) Phages infecting commensal bacteria and common viruses (eg Rhinoviruses and influenza) are highlighted in bold.

 

 

Virus
T
E
E
I
S
E
V
K
M 

Simian immunodeficiency virus  239

APP Homo sapiens
 
 
 
 
 

Epi

E
E
E

Influenza A virus Chicken

BAH03519 Goose

ABJ96738 Duck

ABJ96735

 
*
*
*
*
*
*
*
 

Synechococcus phage S-PM2  YP_195120

 
*
*
*
*
*
*
 
 

Influenza Rio ADE75392

 
*
*
*
 
*
*
*
 
Influenza A virus Hong Kong BAJ07997
Influenza A virus Egypt ADG21445 and many Avine influenza viruses
 
*
*
*
*
 
*
*
 
Bacillus phage NP_046598
 
*
*
*
*
*
 
 
*
Bornavirus ADB84600
 
 
*
*
 
*
*
 
*
Spiroplasma phage SVGII3 CAI94596
 
 
 
 
*
*
*
*
*
Synechococcus phage Syn5  ABP87933
 
 
 
 
 
 
*
*
*
Listeria phage YP_002261477
Aeromonas phage NP_944230
Enterobacteria phage AAN28262
 
 
 
 
 
*
*
*
*
Influenza B virus ABL76812 (Both)
 
*
*
*
*
 
 
 
 
Influenza B virus ACF54229 (Both)
 
 
 
*
*
*
*
 
 

Chlamydia trachomatis

Homo sapiens protein tyrosine phosphatase, receptor

Human papillomavirus type 16

Human papillomavirus type 6b

Human respiratory syncytial virus
 
 
 
 
 
Epi
E
N
L
Influenza Rio ADE75392
 
*
*
*
-
*
*
-
L
Mycobacterium phage ADA83789
Streptococcus phage NP_056710
 
 
*
*
*
*
-
N
L

Bacillus phage TP21-L YP_002333578

Borna virus ACG59353

Campylobacter phageCBJ94264

Corynebacterium phage YP_001468961

Enterobacteria phage Fels-2 YP_001718743

Enterobacteria phage phiEco32 YP_001671828

Liao ning virus YP_460028

Menangle virus YP_415513

Synechococcus phage S-PM2 YP_195115

Unidentified Fusellovirus AAL24816

 
 
 
*
*
*
*
N
 
Synechococcus phage YP_195115
 
 
*
*
*
*
*
N
 

Respiratory syncytial virus ACO83301

Human adenovirus 13  BAG48790, 17 ABQ00199 , 38 BAG48815, 39 BAG48816, 47 BAG48824

Hantavirus Yakeshi-Mm-59 AAB22506

Pseudomonas phage LUZ24

YP_001671894

Puumala virus ABO09803

Muju virus ABM92784

Dobrava-Belgrade virus ADA68892

Flanders virus AAN73285

Clostridium botulinum D phage ZP_04863764

Tacaribe virus NP_694849
 
 
 
 
*
*
*
N
L

Borna Virus ACG59353

 
 
 
 
*
*
*
N
 

Acanthamoeba polyphaga mimivirus YP_001426695

Human adenovirus 41 AAA42440

Beilong virus AAA42439

Fer-de-lance virus NP_899661

Pichinde virus ABU39911

Influenza virus Illinois ABI83868|

Rhinovirus C  ACR14890

Human rhinovirus 28, ABF51202

Human Rhinovirus 68, ACU27211

and Rhinovirus .sp
 
 
 
 
 
*
*
N
L
Enterobacteria phage AR1 BAI83009
Synechococcus phage YP_003097343
Enterobacteriaphage YP_002853956
Streptococcus phage 858 YP_001686831
Enterobacteria phage T4 BAA23634
Enterobacteria phage AR1 BAI83009
Synechococcus phage S-RYP_001957167 201phi2-1p448
Pseudomonas phage YP_001957167 
Enterobacteria phage RB32 YP_238518          
Streptococcus phage 2972 YP_238518

Bordetella phage NP_958690 

 
 
 
 
 
*
*
N
L
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 7 The effects of the Swedish mutations on homology to bacterial proteins. Protein accession numbers are provided  and amino acid matches are indicated by the asterisks or by the red letter of the mutant amino acid. Commensal or common soil bacteria are highlighted in bold.

 

Bacteria
T
E
E
I
S
E
V
K
M 

Atopobium Parvilum C8WAI5

*
*
*
*
*
*
*
*
 

Bermanella maris Q1N288

Shewanella violacea

D4ZM52

 
*
*
*
 
*
*
*
*

Vibrio furnissii C9PJ26

 

 
 
*
*
*
*
*
*
*
Lactis subsp Q031F7
Lactocococcus cremoris 

A2RIQ5 Same for both

*
*
*
*
*
*
 
 
 
Bacillus anthracis C3PD86
Bacillus thuringiensis C3HJR4
Bacillus thuringiensis serovar pondicheriensis C3GK36
Baciillus Cereus C2THS7 several strains
 
*
*
*
 
*
*
*
*

Clostridum tetani Q896K9

Oceanobacillus Q8CV16

 
*
*
*
*
*
*
*
 
Colwellia psychrerythraea Q487K7 
Enterococcus Faecium D3LK32
Ricketsia Typhi Q68XP3
Rickettsia Prowazekii O05942
Photorabdus luminens Q7N0P2 Same for both
*
*
*
*
*
*
*
 
 

Streptobacillus moniliformis

D1AV81

 
*
*
*
*
*
*
*
 
Leptotrichia Buccalis 

C7NE35 Rumibococcus Sp C6JEQ4 Streptococcus pneumoniae 

ABJ55426

Sams for both

 
 
*
*
*
*
*
 
 
Clostridium beijerinckii A6LY25 Sanme for both
 
*
*
*
*
*
*
*
 
 
Planctomyces maris A6C251
 
 
 
 
*
*
*
*
*
*

Leptospira biflexa B0SKY9 Sane for both

 

 
*
*
*
*
*
 
 
 

Mycoplasma hominisD1J7S2

 

 
 
*
*
*
*
*
*
 
Sodalis glossinidius Q4LC19 Same for both
 
*
*
*
*
*
*
 
 
 

Nodularia spumigena A0ZE12 Same for both

 

*
*
*
*
*
 
 
 
 

Streptococcus pneumoniae ZP_01821444 Same for both

 
*
*
*
*
*
 
 
 
 
T
E
E
I
S
E
V
N
L 
Fusobacterium sp C3WJ64
 
 
*
*
*
 
*
*
N
L
Fusobacterium mortiferum C3WDH2
 
 
*
*
*
*
 
*
N
L
Acidobacterium psulatum C1F5P2
 
*
*
*
*
*
*
 
N
L
Corynebacterium matruchotii C5VDU4
Escherichia coli O1 57 H7 Q8X597
Escherichia coli O6 Q8FGX7

Escherichia coli (strain UTI89 / UPEC) Q1RB23

Escherichia coli O6 Q0TH59 and numerous other E.Coli strains

Shigella flexneriQ83RH3 Helicobacter hepaticus Q7VIZ4

Staphylococcus haemolyticus Q4L6V6

Trichodesmium erythraeum Q10V04

 
*
*
*
*
*
*
N
 
Bacteroides thetaiota Q8A9X8
Anaerococcus lactolyticus C2BI02
 
 
 
*
*
*
*
*
N
L
Synechococcus sp. Q7U980
 
 
*
*
*
*
*
*
-
L
Listeria grayi C2BZ78
Streptococcus pneumoniae ZP_01817518 
 
 
 
*
*
*
*
N
L
Citrobacter Youngae D4B9G4
Pseudoalteromonas atlantica Q15N87

Pseudomonas chlororaphis P31521

Pseudomonas fluorescens C3K287
Rhodobacter sphaeroides A4WVX1
Robiginitalea biformata A4CHQ4
Streptococcus pneumoniae CAI34213
 
 
 
 
*
*
*
N
L
Streptococcus pneumoniae ZP_02717209
 
 
 
*
*
*
*
N
 

 

 

 

 

 

Table 8

Viral proteins lining up with autoantigens from Chronic obstructive pulmonary disease, myasthenia gravis, multiple sclerosis and pemphigus vulgaris and to mutant proteins from polyglutamine repeat disorders (Huntington’s disease, Dentatorubropallidoluysian atrophy,  Kennedy disease and Spinocerebellar ataxias) and from cystic fibrosis. APOE4 is included as an example of a risk factor in a number of polygenic diseases. Accession numbers and the aligning sequences are shown with references where the virus has been implicated in the relevant disease. The polyglutamine expansions also increase the antigenicity of the resultant peptide with each triplet QQQ addition.

 

Autoantigen

Viral Homolog

Sequence

Involvement

Myaesthenia Gravis Nicotinic receptor CHRNG NP005190 acetylcholine receptor subunit gamma

 

ABC71426 Human echovirus 18

AF427971 Human coxsackievirus B1

FDWQNC

 

 ?

AF507093Bovine rotavirus G10          

IVVNA

 ?

CAF24822 Human herpesvirus 1

ABW83347 Human herpesvirus 2

R-R--RDY-G- VLRV

                       

Anti nicotinic receptor antibodies isolated from myasthenia patients cross react with HSV-1 glycoprotein D (119)

ACC94304 Tamiami virus

EEALTT

 ?

NP_477882 Shrimp white spot syndrome virus

DIVLEN

 ?

ADD94092  uncultured phage

NQEERL

 ?

Ssystemic lupus erythematosus  XRCC6 NP_001460

ADD65207.1   glycoprotein     Sandfly fever Naples virus] AAN06959.1         polyprotein       Toscana virus]

TLFSALLI

 

?

>emb|CAA37487.1| hypothetical protein [Non-A, non-B hepatitis virus]

VPQEEEL

 

?

BAA77426.1   ORF2             Torque teno virus]

LLR-VRAK

 

?

ACS29433.1   polyprotein      Hepatitis C virus]

RDSLI-LV

 

Lupus is frequently reported in Hepatitis C patients {Ramos-Casals, Munoz, et al. 2009 1801 /id}

AAA52748.1   polyprotein      Hepatitis C virus subtype 1b]

PPDYNP

 

NP_149906.1  443R   Invertebrate iridescent virus 6]

TRTF-TSTG

And

DIISIA---DL

?

AAC35885.1   protease          bovine adenovirus 10]

SEEELK-HI

 

?

Pemphigus Vulgaris Desmoglein-3 NP_001935

 

Human herpesvirus 1

VNKTIT

Occasionally associated with HSV-1 (120)

ABB22271 Ovine herpesvirus 2

STGGTN

 ?

AAP82014 Suid herpesvirus 1

TGALAI

 ?

CBJ94251 Campylobacter phage

KFKKLA

 ?

AAX8491  Xanthomonas phage

K-LVDYIL

 ?

YP_001950153  Ralstonia phage

QLRGSHT

 ?

NP_958691 Bordetella phage

SGQSGTM

 

 ?

NP_112040 Enterobacteria phage

IEGAHPE

 

 ?

Chronic obstructive pulmonary disease Elastin NP_000492.2 elastin isoform a precursor

 

ABI15777. Encephalomyocarditis virus

NP_653077 Equine rhinitis B virus   

ABB97066 Mengo virus

 

GLPYTT

 

?

ACI22601 Influenza B virus

SILH-SRP

 

Picornavirus ,influenza; respiratory syncytial virus; corona viruses, parainfluenza; adenovirus and human metapneumovirus detected during COPD exacerbation (121)

BAE96916  Respiratory syncytial virus

Y-AAKA A     

 

AAA47928 Theiler's encephalomyelitis virus

PGFGL-P

 

?

NP_044050 Molluscum contagiosum virus subtype1

IFPGGA

 

 ?

BAH15164  Serratia phage

GLSPIF

 

 ?

CAM12729 Zucchini yellow mosaicvirus

VGGIPT

 

 ?

ADF28539 Human TMEV-like cardiovirus :

ACO92355 Saffold virus

PGFGLS

 

?

ABD73306 Gremmeniella abietina type B RNA virus

PIKAPKL

 

?

NP_612874 Clostridium phage

G+GLPYTT

 

?

BAA03030 Orgyia pseudotsugata single capsid nuclopolyhedrovirus

APRPGV

?

Multiple sclerosis Crystallin CRYAB

 

EBNA3 Epstein-Barr virus

DQFFG

Implicated (122)

D2XR26 Bacillus phage

HSPSRL

 ?

9PARAQ84747 Human parainfluenza virus 1

R-PSFLR

Implicated (123)

C9WSX19 Norovirus dog

SLSSDGV

Dog ownership has been

 linked to multiple sclerosis (124;125)

Multiple sclerosis Myelin associated glycoprotein MAG

AAB58805

 

YP_164320 Pseudomonas phage

AEDGVYA

 

?

YP_003406894 Marseille virus

KYYFRG

 

?

CAA24862.1   Human herpesvirus 4 (Epstein Barr)

PAVLGR--E

 

Implicated (122)

 

P25939 Human herpesvirus 4 (Epstein Barr)

LRGQ-QAP

 

CAA66845 Human herpes virus 4  (Epstein Barr)

DEGTWV

 

AAD51697 Human herpesvirus 4 (Epstein Barr)

PSSIS

 

ABV71654.Human herpesvirus 5 (Cytomegalovirus)

CP+LRP-LS- L

Implicated: Seropositivity predicts a better outcomein Multiple Sclerosis (Beneficial virus ?) {Zivadinov, Nasuelli, et al. 2006 1800 /id}

AAR31274 Human herpesvirus 5 (Cytomegalovirus)

GKYYF-R-D

YP_015543 Pyrobaculum spherical virus

YITQTR

 

?

Multiple Sclerosis  MBP NP_001020252 myelin basic protein isoform 1

 

ACO87999 Hirame rhabdovirus

GRGLSL

?

ADE45455 Polyomavirus HPyV7

RSGSPM

?

YP_073799  Human herpesvirus 7

PSQRHGS

Detected in MS tissue (126)

NP_042301 Southern cowpea mosaic virus

PGRSPLP

 

 ?

YP_143172 Acanthamoeba polyphaga mimivirus

IGRFFGG

 

 ?

ABB22292   Ovine Herpesvirus 2 NP_065571 Alcelaphineherpes virus1

FFKNIV

 

 ?

JC polyomavirus

PRTPPP

 

Seropositivity in some Multiple sclerosis patients (127)

BAA00490  Ornithogalum mosaicvirus

TQDENP

 

?

YP_003280846  Helicobasidium mompa endornavirus1

DSIGRF

 

?

CAA32420 Simian rotavirus

ARTAHY

 

?

YP_002117760  Pseudomonas phage

IVTPRT

 

 ?

YP_164431 Bacillus phage

GRASDY

 

 ?

NP_570206 Swinepoxvirus ACV04605  Nakiwogovirus

TLSKIF

 

 ?

YP_214645 Prochlorococcus phage

GRSPLP

 

 ?

YP_142835 Acanthamoeba polyphaga mimivirus

LDSIGR

 

 ?

ACZ8140 Moussavirus

TAHYGS

 

 ?

BAA77241 Broadbean wilt virus2

RASDYK

 

 ?

Multiple sclerosis Myelin Oligodendrocyte protein MOG

 

NP_944019 Aeromonasphage

AMELK

 ?

ADA81168 Staphylococcus phage

VLGPLV

 ?

NP_690686 Bacillus phage

LVALII

 ?

ABO87130 Hepatitis delta virus

KDQDG

 ?

ADE60693 Rice stripe virus

SRVVHL

 

 ?

ACA24946 Swine parainfluenzavirus3

RDHSY

 

 ?

AAL89267  Shrimp whitespot syndrome virus

NLHRTF

 

 ?

NP_569759 Mycobacterium phage

ELLKDA+G

 ?

Multiple sclerosis NP_000524

myelin proteolipid protein isoform 1

 

BAB83467 Chlorellavirus

SATVTGGQ

 ?

CAG70345 Bovine viral diarrhea virus 1

VPVYIY

And

GITYA

 

 ?

YP_001111042Burkholderia phage

FNTWT

 ?

AF310938 Powassanvirus 

NP_620108 Langatvirus

CSAVPV

 ?

AAW33310 Human adenovirus4

GLLEC

Associated with relapse in multiple sclerosis (128)

ABO42303 Avian meta pneumo virus

KTSA-SIGSLC

 

 ?

ABU82778 Human metapneumovirus

KTSA-SIGSLC

 

 ?

YP_002241563  Mycobacterium phage Butterscotch 

YP_002241480 Mycobacterium phage Troll4 

YP_655259 Mycobacterium phage PBI1

KNYQDY

 

 ?

YP_717772  Synechococcus phage

YQDYEY

 ?

YP_001129421 Human herpes virus 8  (Kaposi’s sarcoma virus)

PFASL-A

And NFAVL

 ?

ABI35813 Human meta pneumovirus

KTSA-SIGSLC

 ?

YP_002241961 Mycobacterium phage Gumball 

YP_001936156 Mycobacterium phage Adjutor

KNYQDY

 

 ?

AAK69175 Bovine viral diarrhea virus 1

VPVYIY

 

 ?

YP_71777 Synechococcus phage syn9

YQDYEY

 

 ?

ABB89216 Human herpes virus 4 (Epstein Barr)

AHSLE

 

Implicated (122)

Polyglutamine repeats, Huntinhton’s disease, spinocerabellar ataxias, Dentatorubropallidoluysian atrophy, Kennedy disease Querey = qqqqqqqqqqqqqqqqqqqqqqq

AAS86764 Zantedeschia mild mosaic virus

QQQQQQQQQQQQQ-QQQQQQQQQ

 

AAQ96572  Vibrio phage VP16C

QQQQQ--------QQQQQQ----QQQQQQQQQQQQ

 

YP_001468520 Listeria phage A511

QQQQ----------QQQ---QQQ--QQQ--QQ--------QQQQQQQ

 

YP_398993 Enterobacteria Phage

QQ---QQQQQQQQQQQQQQQQQQQ

 

gbAAC57158 Human herpesvirus 8 type M

+QQQQ+QQQQ—QQQQ—QQQQ--QQQQ

AAR14310 Lactococcus phage ul363

Q-QQQQQQ----Q-Q---Q-Q-QQ---QQQ+Q

 

YP_001456769 Corynebacterium phage

QQQ--Q+Q----QQQ--Q+Q-----QQQQ-----QQQ

 

NP_116331 T2  Tupaiid herpesvirus 1

QQQQQQQQQQQQQQQQQQQQQQQ

 

ACO25273  Epizootic haematopoietic necrosis virus

+QQ++QQQQQQQQQQQQ++Q++Q

AAL89066 Shrimp white spot syndrome virus

QQQQQQQ-+QQQQ-+QQQQQQQQ

 

YP_001218813 Pseudomonas phage

QQ--Q-Q--QQ--QQQQQQQQ-Q

 

embCAA52472 Human papillomavirus type 3

+QQQQQQQQQQQQQ+Q

CAA75466Human papillomavirus type 77

QQQQQQQQQQQQQ

 

Human adenovirus 1

++QQQQQQQQ++------Q+Q

AAA79432   Human papillomavirus type 29

QQQQQQQ+QQQQQQQ

 

CAA75466 Human papillomavirus type 77

QQQQQQQQQQQQQ

 

AAL50729 Human herpesvirus 6B

QQQQQ+QQQQ

NP_050183 Human herpesvirus 6

QQQQQ+Q-QQQ

ADB84736 Human herpesvirus 5

QQQQQQQ+Q

 

ABQ51392  Human rhinovirus sp.

QQQ

Cystic fibrosis  CFTR

 

AAB59808 Vaccinia virus 

CAA53834  Variola virus

GT-IKENII---G

 

YP_003090182 Burkholderia phage KS9

IIGVSY-DE

Burkholderia infection has been related to Cystic fibrosis (126;129)

YP_001504144 Enterococcus phage

DEYR-RSVI

 

 

ACF59816 Human parainfluenza virus 4b

GTIKE-II

 

 

YP_908809 Staphylococcus phage 

YP_002003602  Escherichia phage rv5

KENIIG

 

 

NP_046572  Bacillus phage

YP_052931  Palyam virus

BAA34933  Chuzan virus

GTIKEN

 

 

ABD63811Lactococcus phage YP_717768  Synechococcus phage

VSYDEY

 

 

AAM4760 Dendrolimus punctatus cypovirus 1

 

MPGTIK

 

 

 

YP_00183702  Enterobacteria phage

TIKENI

 

 

YP_003358383 Pseudomonas phage YP_002456113 Erwinia phage

GVSYDE

 

 

Polygenic diseases APOE4  gi15826311 pdb 1B68 A Chain A, Apolipoprotein E4

ACE82482 Hepatitis C virus subtype 1a

GADMEDV

 

 

ACT53109 Hantavirus Jurong ACO37156 Seoul virus

ET+KELKA

 

 

NP_932306 Botrytis virus X

ALM-ETMK

 

 

NP_116510  Lactococcus phage

K-EL+EQLTP

 

 

AAN03856 Adeno-associated virus-8

LS-IRE-LGP

 

 

YP_00292273  Burkholderia phage

Q--WQSGQ

 

YP_002455799 Lactobacillus phage

MKELKA

 

YP_003358506 Shigella phage

VQTL-EQV+E     

 

 

DAA06495 Human herpesvirus 5

DDL—R-LAVYQA

 

 

ABI63513 Human herpesvirus 1

RLA-HLR

And KRLLR

 

Binds to APOE (see text)

AAK50002 Human herpesvirus 8

LA-S-LR-LRKR

 

AAT07716 Human herpesvirus 3 (Varicella Zoster)

LEEQLT--A

 

 

ACM48047 Human herpesvirus 5

LRD-D--DLQKR

 

 

YP_001129382  Human herpesvirus 8

G+RWEL

And  LVEQ--VR

 

 

AAY41102 Human herpesvirus 4

G-D-EDVR

 

 

 

Figure 1

 

 

 

 

 

Figure 2

 

 

 

Viral protein matches to different regions of the beta-amyloid peptide in relation to the predicted B Cell Epitope antigenicity. Predicted epitopes are marked with an asterisk and the Y-axis is an index of antigenicity. The VGGVV epitope has been used to label beta-amyloid and is marked + as are other short epitopes used to label beta-amyloid (QKLV, FFAE, IIGL) Other short epitopes used to label beta-amyloid include MGGVV, VGGVV, MVGGVV, VGGVV and GGVVIA). The viruses and bacteria in black boxes represent those where vaccination was reported to reduce the incidence of Alzheimer’s disease. These alignments are to viral proteins rather than to epitopes within the vaccine. The arrows represent the beta-amyloid cleavage sites of the catalytic beta-amyloid autoantibodies isolated from Alzheimer’s disease sera. H*↑Q is the major site of catalysis.  Note that cancer and plant viruses overlap this region. Burk= Burkholderia Phage; Camp Phage = Campylobacer Phage; HumRespSyn = Human respiratory syncitial Virus; HepC = Hepatitis C; HIV = Human Immunodeficiency Virus; HSV-1 = Herpes simplex (Human Herpesvirus 1); Mycobact = Mycobacteria phage; Strep = Streptococcus phage;  C.Tet = Clostridium Tetani, C.Dip = Corynebacterium diphtheriae (See Table 2 for Accession numbers)

 

 

Figure 3

 

Allergenic protein matches to different regions of the beta-amyloid peptide in relation to the predicted B Cell Epitope antigenicity.   Predicted epitopes are marked with an asterisk and the Y-axis is an index of antigenicity .Allergens expressing proteins that match different regions of the beta-amyloid peptide are aligned with their respective matches. The arrows represent the beta-amyloid cleavage sites of the catalytic beta-amyloid autoantibodies isolated from Alzheimer’s disease sera. H*↑Q is the major site of catalysis (see Table 2 for Accession numbers). 

 

 

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