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The Guillain–Barrè peptide signatures: from Zika virus to Campylobacter, and beyond

Authors Lucchese G , Kanduc D

Received 15 April 2017

Accepted for publication 31 May 2017

Published 1 August 2017 Volume 2017:9 Pages 1—11

DOI https://doi.org/10.2147/VAAT.S124535

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Jonathan Dinman



Guglielmo Lucchese,1 Darja Kanduc2

1Brain Language Laboratory, Freie Universität Berlin, Berlin, Germany; 2Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy

Abstract: Scientific attention has focused recently on the link between Guillain–Barrè syndrome (GBS) and Zika virus (ZIKV). Two related questions emerged: 1) what triggered the violent 2014 outbreak of a virus, which, first identified in 1947, had caused only a limited number of documented cases of human infection until 2007 and 2) which molecular mechanism(s) relate ZIKV active infection to GBS, an autoimmune inflammatory polyradiculoneuropathy. Capitalizing on the increased interest on ZIKV and hypothesizing the involvement of autoimmune mechanisms, we searched for minimal epitopic determinants shared between ZIKV and other GBS-related pathogens – namely, Epstein–Barr virus, human cytomegalovirus, influenza virus, Campylobacter jejuni, and Mycoplasma pneumoniae, among others – and human proteins that, when altered, have been associated with myelin disorders and axonopathies. We report a considerable peptide matching that links GBS-related pathogens to human proteins related to myelin disorders and axonopathies. Crucially, the shared pentapeptides repeatedly occur throughout numerous epitopes validated as immunopositive by a conspicuous scientific literature. The data support a scenario where multiple different infections over time and resulting multiple cross-reactions may contribute to the pathogenesis of GBS. In practice, previous infection(s) might create immunologic memory able to trigger uncontrolled hyperimmunogenicity during a successive pathogen exposure. ZIKV pandemic appears to be an exemplar model for a proof-of-concept of such multiple cross-reactivity mechanism.

Keywords: peptide sharing, GBS-related human proteins, GBS-related pathogens, multiple cross reactivity, hyperimmunogenicity

Introduction

Zika virus (ZIKV) was discovered in 1947 and has been considered of little or no clinical importance until 2007, a date that marks the beginning of epidemics that caught scientific and clinical communities by surprise.1 Among the pathologic sequelae, Guillain–Barré syndrome (GBS) in adults appears to be a clinical outcome following ZIKV active infection.27

How this neuropathologic outcome and the flavivirus infection may be linked at the molecular level is unknown. Actually, some authors have even interpreted the co-occurrence of ZIKV infection and GBS as a temporal coincidence rather than a causal relation.8 The issue is further complicated by the fact that GBS – although described for the first time in 18599 – still presents, beyond its association with ZIKV, a largely unknown etiology. Genetic factors have been hypothesized to constitute a causal platform leading to the disease.10,11 However, research on candidate genes that could plausibly be involved in the pathogenesis of GBS has not been conclusive. For instance, increased susceptibility to GBS in association with polymorphisms in CD1, low-affinity immunoglobulin gamma Fc region receptors II-a and II-b (FcRII-a and FcRII-b),1214 and interleukin-10 genes still awaits validation.1517

In parallel, a large body of research has investigated the possible association between GBS and infections. In particular, Campylobacter jejuni and Mycoplasma pneumoniae infections have been related to the disease,1822 most possibly through autoimmune cross-reactive mechanisms.2326 At a lesser extent, human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) might also be involved in GBS. Indeed, although many reports did not relate HCMV to GBS,2729 nonetheless, numerous cases of HCMV-GBS association have been described in transplant recipients and during pregnancy.3036 Moreover, a prospective cohort study described 63 (12.4%) HCMV-GBS cases out of 506 patients with cases of GBS, with patients with HCMV-GBS more likely to be young – <35 years old in most of the cases – and female.37 Similarly, numerous clinical case reports describe GBS associated with EBV infection.3842

However, it remains unclear how such infectious pathogens – which are largely widespread and sluggishly latent worldwide4348 – can, all of a sudden, attack the host causing the complex pathologic picture of the GBS.

Based on the autoimmune context that connects infections to GBS, we recently analyzed ZIKV polyprotein for peptide sharing with human proteins that, when altered, may associate with GBS-like syndromes and found large peptide overlap suggestive of a great potential for autoimmune cross-reactivity.49 Here, we use the peptide platform common to ZIKV and GBS-associated human proteins and search for minimal immune determinants that are additionally shared with infections related to GBS such as the above-mentioned C. jejuni, HCMV, EBV, and M. pneumoniae. The scientific rationale is that different infectious pathogens might evoke a succession of immune responses converging on identical epitopic sequences and characterized by a progressively more rapid production of increasingly powerful antibodies on subsequent encounters with the same epitopic targets. Then, sharing of identical cross-reactive epitopes with host proteins can result in amplified cross-reactions and consequent severe diseases, thus explaining the violence of the otherwise asymptomatic ZIKV infection.50

Methods

Analyses were conducted on human proteins related to GBS and retrieved from UniProtKB Database (http://www.uniprot.org/)51 using “myelin, (de)myelination, axonal neuropathy” as keywords (Table S1), as already detailed elsewhere.50 References for disease involvement are available at http://www.uniprot.org/. Human proteins are indicated by the UniProt Accession name.

A set of pathogen proteomes was chosen for analyses based on the following criteria:

  • belonging to infectious agents that have been reported as related to or concomitant, even occasionally, with GBS, ie, C. jejuni,18,19 M. pneumoniae,18,2022 HCMV,18,3037 EBV,18,3842 hepatitis E virus, genotype 1 (HEV),52 human papillomavirus type 16 (HPV16),53 influenza viruses,54 dengue virus (DENV),55 West Nile virus (WNV),56 yellow fever virus (YFV),57 and varicella zoster virus (VZV);58
  • for which proteome completeness has been established;
  • with experimental evidence at protein level;
  • belonging to the Swiss-Prot section reviewed by UniProtKB.

The pathogen proteomes are as follows (in alphabetical order, with abbreviations, number of proteins, number of amino acids (aa), and taxonomy ID): C. jejuni, 1623 proteins, 507643 aa (192222); DENV, 10 proteins, 3392 aa (11059); EBV, 109 proteins, 51458 aa (10377); HEV, 3 proteins, 2467 aa (652674); HCMV, strain Merlin, 168 proteins, 63460 aa (295027); HPV16, 8 proteins, 2426 aa (333760); influenza A virus, H1N1, 12 proteins, 4788 aa (211044); influenza A virus, H5N5, 12 proteins, 4809 aa (93838); influenza B virus, 11 proteins, 4718 aa (518987); M. pneumoniae, 687 proteins, 239888 aa (272634); VZV, 69 proteins, 35782 aa (10338); WNV, 13 proteins, 3430 aa (11082); YFV 13 proteins, 3411 aa (11090); and ZIKV, 13 proteins, 3419 aa (64320). Proteomes are described in detail at http://www.uniprot.org/.51

Peptide matching analyses were conducted using the pentapeptide as a minimal immune unit5961 and utilizing the elsewhere described pentapeptide platform shared between ZIKV and human proteins that, when altered, may associate with GBS.49 In brief, GBS-related proteins were obtained from UniProtKB51 using the keywords “myelin, (de)myelination, axonal neuropathy”. Then, the primary aa sequence of each ZIKV protein was dissected into pentapeptides overlapping each other by four residues. For example, ZIKV protein C (Q32ZE1, aa 2-104, KNPKEEIRRIRIVNMLKRGVARVNPLGGLKRLPAGLLLGHGPIRMVLAILAFLRFTAIKPSLGLINRWGSVGKKEAMEIIKKFKKDLAAMLRIINARKERKRR) was sequentially dissected into KNPKE, NPKEE, PKEEI, KEEIR, and so forth until its last pentapeptide ERKRR, for a total of 99 pentamers. At the end, the 12 ZIKV proteins (prM considered as one protein) yielded 3370 pentapeptides. The same procedure was applied to calculate the number of pentapeptides present in the pathogen proteomes described earlier.

The 3370 ZIKV pentapeptides were probed for occurrences within the set of human proteins related to GBS using PIR peptide match program (http://research.bioinformatics.udel.edu/peptidematch/index.jsp).62 A total of 222 ZIKV pentapeptides were found to occur throughout 97 human proteins related to GBS. The 97 human proteins related to GBS and sharing pentapeptide(s) with ZIKV have been previously detailed.49

The pentapeptide platform common to ZIKV and GBS-related proteins was used to search for commonalities with GBS-related pathogens. That is, each of the 222 ZIKV pentapeptides shared with the 97 GBS-related proteins was analyzed for occurrences in the pathogen proteomes of infectious agents that had been selected as described earlier.

The immunological potential of the peptide sharing was investigated using the Immune Epitope Database (IEDB; www.iedb.org) resource.63 Only epitopes that had been experimentally validated as immunopositive in the human host were considered.

Results

Pentapeptide(s) common to ZIKV, GBS-related human proteins, and GBS-related pathogens.

Table 1 shows the occurrences of the ZIKV pentapeptides shared with the 97 GBS-related proteins in the analyzed infectious agents. It can be seen that, with the exception of influenza B virus, the analyzed GBS-associated pathogens share pentapeptides common to ZIKV and human GBS-related proteins.

Table 1 Pentapeptides common to ZIKV, GBS-related human proteins, and GBS-related pathogens

Notes: aPentapeptides with multiple occurrences in bold. bTwo HEVs, genotype 3, taxonomy IDs 509615 and 512345, share only 2 pentapeptides (ALRGL and LRGLP).

Abbreviations: ZIKV, Zika virus; GBS, Guillain–Barrè syndrome; HPV16, human papillomavirus type 16; HEV, hepatitis E virus, genotype 1; EBV, Epstein–Barr virus; VZV, varicella zoster virus; HCMV, human cytomegalovirus; DENV, dengue virus; WNV, West Nile virus; YFV, yellow fever virus.

Numerically, 135 out of 222 pentapeptides shared between ZIKV and the set of human GBS-related proteins occur and often recur throughout the pathogens under analysis for a total of 206 multiple occurrences. As previously observed,6467 such pentapeptide sharing is extremely high and unexpected given that the probability E of a ZIKV pentapeptide to occur simultaneously in the set of the 13 GBS-related pathogens and in the set of the 97 human GBS-related proteins is 6977141836772461e-6, ie, it is close to zero (Box 1). This infinitesimally low value is in sharp contrast with the actual data displayed in Table 2. As a matter of fact, Table 2 highlights an intense pentapeptide sharing that underlies a multiple cross-reactivity platform among the analyzed pathogens and the human host.

Box 1 Theoretical probability E of a ZIKV pentapeptide to occur simultaneously in the set of the 13 GBS-related pathogens and in the set of the 97 human GBS-related proteins under analysis

Abbreviations: ZIKV, Zika virus; GBS, Guillain–Barrè syndrome; aa, amino acids.

Table 2 Epitopes experimentally validated as immunopositive in the human host and containing pentapeptide(s) common to ZIKV, GBS-related human proteins, and GBS-related pathogens

Notes: aEpitope IEDB IDs are listed in ascending numerical order. Details and references are available at http://www.iedb.org/idsearch.php. bEpitope peptide sequences are given in one letter code. cShared peptide fragments are given in capital letters.

Abbreviations: ZIKV, Zika virus; GBS, Guillain–Barrè syndrome; IEDB, Immune Epitope Database.

Immune potential of the pentapeptides common to ZIKV, GBS-related human proteins, and GBS-related pathogens

Such a high potential for cross-reactions appears likely also in view of the fact that most of the 135 pentapeptides detailed in Table 2 not only often recur among the GBS-related pathogens (eg, the pentapeptides EEIRR, AAARA, ALAGG, GAGKT, GALEA, GPSLR, and GSASS given in bold in Table 1) but are also present in hundreds of epitopes experimentally validated as immunopositive in the human host. Table 2 shows a limited representative list of such immunopositive epitopic sequences.

Discussion

Starting from 2000,64 our laboratory described a massive peptide overlap between proteins from infectious agents and the human proteome,65 thus calling attention to the cross-reactivity issue in immunology. In fact, the magnitude of such a peptide sharing leads to predict a high extent of cross-reactive immune responses following infections in the human host.6672

Here, we focus on the issue of multiple cross-reactivity and analyze the molecular connections between infectious pathogens related to GBS. We report on the presence of minimal immune determinants in the human host and repeatedly shared among infectious agents so different as the flaviviruses ZIKV, DENV, WNV, and YFV and the bacteria M. pneumoniae and C. jejuni. Such intrapathogen peptide commonality may originate multiple cross-reactions having the same peptide sequences as epitopic targets. The immunological implications are that immune responses elicited by different successive infections may add up with intensified avidity and affinity at the level of cross-reactive sites, thus exacerbating autoimmune attacks in the host.

The extent of the autoimmune damage emerges from the analysis of the human proteins involved in the sharing, most of which are crucial components of the neurological network. An example among the many is the pentapeptide LAGAL that is shared by ZIKV, EBV, M. pneumoniae, and C. jejuni and is also present in three human proteins involved in myelin disorders, ie, CGT, GFAP, and MTMR2 (Tables S1 and S2).

  • CGT or 2-hydroxyacylsphingosine 1-beta-galactosyltransferase is involved in the synthesis of sulfatide 3-O-sulfogalactosylceramide,73 which is essential for paranodal junction formation and for the maintenance of ion channels on myelinated axons.74 Of note, the sulfatide blocks the binding of C. jejuni DNA-binding protein to myelinated nerves, a reaction that has been associated with C. jejuni-related GBS;75
  • GFAP or glial fibrillary acidic protein has been reported to be a marker of axonal GBS and outcome;76
  • Myotubularin-related protein 2 (MTMR2) is a phosphoinositide-3-phosphatase that, if altered, associates with demyelinating peripheral neuropathy characterized by excessive redundant myelin, also known as myelin outfoldings.77,78 MTMR2 appears to negatively regulate membrane homeostasis in Schwann cell myelination.79

Another myotubularin-related protein, namely MTMR5, shares eight pentapeptides with ZIKV (eg, AVLLR, GPSLR, GLLIV, LQDGL, REEGA, SEELE, SLGLI, and VLSMV) and many of the said pentapeptides are also present in infectious agents (Table 1). MTMR5 pentapeptide sharing is noteworthy. Indeed, alterations of MTMR5 are involved in demyelinating neuropathies79 and, in addition and most interestingly, lead to impaired spermatogenesis.8082 This datum might be a hint for widening the study of the still obscure reasons for gender differences in GBS pathogenesis.83 In this perspective, also future studies that extend analyses to non-peptidic GBS epitopes warrant attention. For example, B4GN1 or beta-1,4-N-acetylgalactosaminyltransferase 1 plays a role in spermatogenesis and, when altered, in male infertility;84 is involved in the biosynthesis of gangliosides85 and produces a ceramide trisaccharide (N-acetyl-d-galactosaminyl- (N-acetylneuraminyl)-d-galactosyl-d-glucosylceramide) that is present in non-peptidic structural GBS epitopes (IEDB IDs: 139429 and 143251).

Although space precludes a detailed discussion of the data reported in Table 1, a final note is due with regard to WNV that hosts 44 out of the 135 pentapeptides common to ZIKV and GBS-related human proteins (Table 1). WNV infections may cause acute flaccid paralysis through a pathogenic mechanism that most possibly involves disrupted glutamate transporter expression in the spinal cord.56 Hence, it draws our attention the presence of three pentapeptides (namely ALRGL, GAALR, and LLGLL) that are present in the amino acid transporter SATT (or SLC1A4 or ASCT1) (Table S2). SATT is essential in brain for d-serine transport86 and is mostly expressed in hippocampal pyramidal and dentate granule neurons, and, in the cerebellum, Purkinje cells and their dendrites, thereby suggesting a role in pathophysiological processes that involve glutamate toxicity.87 Indeed, activation of N-methyl-d-aspartate receptors (NMDARs) by synaptically released l-glutamate requires occupancy of coagonist binding sites in the tetrameric receptor by either glycine or d-serine, so that altered SATT and, thereby, altered d-serine flux in the brain would alter NMDAR activity. The hypothesis of a potential link between SATT-induced NMDAR alteration and flaccid paralysis seems to find a support in the fact that flaccid paraplegia has been observed in patients with autoantibodies to NMDARs.8890

Conclusion

We observe that the main caveats of the present research are the limited number of the analyzed pathogens and, in addition, the fact that, in front of the tendency of infectious pathogens to mutate, only representative taxonomy types have been analyzed. Hence, the level of intrapathogen multiple cross-reactivity might be even underestimated. A second limitation of the present study is given by the fact that it mainly analyzes peptidic epitopic sequence potentially related to GBS. As a matter of fact, the acute paralytic GBS is also characterized by autoantibodies against glycolipids and gangliosides.91,92

Given these notes of caution, the present study offers a scientific rationale and a methodology to analyze the molecular role of intrapathogen sharing in the pathologic sequelae that may be associated with multiple infections. Indeed, the high serological cross-reactivity that exists among flaviviruses (eg, ZIKV, DENV, WNV, and YFV)93,94 exemplifies the possibility that different infections occurring at different times may sum up onto a same set of epitopic determinants and result in hyperimmunogenicity,95,96 possibly resulting in neurological damage.

Acknowledgments

GL gratefully acknowledges support from the Deutscher Akademischer Austauschdienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG), and the Freie Universität Berlin, Germany. DK’s studies and research have been supported by University of Bari, Italy.

Disclosure

The authors report no conflicts of interest in this work.

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Supplementary materials

Table S1 List of the 97 human proteins related to myelin, (de)myelination, and/or axonal neuropathies and sharing pentapeptides with ZIKV polyprotein (human proteins are reported by UniProt entry, a brief description of function, and aa length)

Notes: Human proteins were retrieved using “myelin, (de)myelination, axonal neuropathy” as keywords. Proteins are indicated by UniProtKB/Swiss-Prot entry names, aa length, and listed in alphabetical order. Details and references for disease involvement are available at http://www.uniprot.org/.

Abbreviations: ZIKV, Zika virus; aa, amino acids; CNS, central nervous system; MRI, magnetic resonance imaging.

Table S2 Pentapeptide platform shared by ZIKV polyprotein and human proteins related to myelin, (de)myelination, and/or axonal neuropathies: 222 ZIKV pentapeptides (in bold) recur throughout 97 proteins (in parentheses as UniProt entry names)

Abbreviation: ZIKV, Zika virus.

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