ReviewZika virus and autoimmunity: From microcephaly to Guillain-Barré syndrome, and beyond
Introduction
In the context of emerging and re-emerging infectious diseases, scientific and clinical attention was called recently [1], [2], [3], [4] to ZIKV infection. In particular, investigating the molecular determinants and mechanisms that might relate acute ZIKV infection to fetal brain damage, i.e., microcephaly [2], [3], [4] appears of foremost importance for understanding ZIKV pathogenicity as well as for developing preventive/therapeutic approaches.
Focusing on the ZIKV-induced immune responses as a possible link to the viral pathologic sequela, this study analyzed the peptide sharing between ZIKV polyprotein and human proteins associated with microcephaly, and used the Immune Epitope DataBase (IEDB) [5] to investigate the immunological potential of the shared peptides. The underlying rationale is that common peptides between a pathogen and the human host may lead to autoimmune pathologies through crossreactivity phenomena following pathogen infection [6], [7], [8].
The results described here (i) document a relevant penta- and hexapeptide sharing between ZIKV polyprotein and human proteins that, when altered, are specifically associated with microcephaly, brain calcifications, and Guillain-Barré-like syndromes, and (ii) support immune crossreactivity as a mechanism involved in the pathologies that may associate with ZIKV active infection.
Section snippets
Peptide sharing between ZIKV polyprotein and human proteins related to microcephaly
Penta- and hexapeptides were used as sequence probes based on the fact that a peptide grouping formed by five-six amino acid (aa) residues can induce highly specific antibodies, and that antigen–antibody specific interaction may depend on just five-six aa of an antigenic protein [9], [10], and pertinent references therein].
Analyses were carried out on ZIKV polyprotein, 3419 aa, NCBI Ref Sequence: NC_012532.1 [11]. Peptide sharing between ZIKV polyprotein and human microcephaly-related proteins
Peptide sharing between ZIKV polyprotein and human proteins related to altered brain calcification
Fetal brain calcifications have been also reported in the pathologic sequela associated with ZIKV infection [44]. Consequently, we also investigated whether the viral polyprotein might share sequences with human proteins involved in altered brain calcification. Applying the research paradigm described above for microcephaly, we captured human proteins related to cerebral calcification from Uniprot (see Supplementary Table 3), and then searched them for peptide sharing with ZIKV.
Table 3 shows
Peptide sharing between ZIKV polyprotein and human proteins related to myelin, (de)myelination, and axonal neuropathies
Following reports linking ZIKV infection to GBS [47], [48], [49], we analyzed the peptide sharing between the virus and human proteins potentially related to GBS related proteins. GBS encompasses a spectrum of neuropathies with variants and subtypes (i.e., Miller Fisher syndrome and Bickerstaff’s brain-stem encephalitis) [50]. Basically, the pathologic features of GBS support a classification that includes demyelinating and axonal subtypes, i.e., acute inflammatory demyelinating polyneuropathy
Conclusions
On the whole, this study powerfully supports an autoimmune etiological component for the brain damage and the neurodevelopmental disturbances recently described in infants following in utero ZIKV infection. De facto, the vast, intense, and widesprad peptide sharing illustrated in Table 1, Table 2 clearly demonstrates that, under conditions of immunoreactogenicity, prenatal exposure to ZIKV infection might result in anti-viral immune responses crossreacting with human proteins that, if attacked,
Take-home messages
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ZIKV infection during pregnancy may cause fetus microcephaly and other brain anomalies.
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ZIKV infection has also been related to Guillain-Barré-like syndromes
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How the viral infection relates to fetal brain malformations and to Guillain-Barré-like syndromes is unknown.
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We describe a massive peptide sharing between ZIKV and human proteins specifically related, when altered, to the ZIKV-induced pathologic sequela.
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Such a massive peptide sharing might lead to crossreactions with consequent autoimmune
Conflicts of interest
None.
Acknowledgemnts
GL gratefully acknowledges support by the Deutscher Akademischer Austauschdienst (DAAD), the Deutsche Forschungsgemeinschaft (DFG), and the Freie Universität Berlin, Germany.
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