Several studies have shown that IDD in CNS can be triggered by viral infection or immunizations. After a variable period of incubation, myelin destruction undergoes courses of remission and exacerbation. MS is a most common disease that compromises CNS myelin sheath (17).
Viral infection can trigger autoimmune diseases through different mechanisms: molecular mimicry, epitope spreading, bystander activation, superantigen production, and inadequate activation of immune response (18). Molecular mimicry can be defined as similar structures shared by a host epitope and microorganism or environmental proteins (18). Using bioinformatics tools, common sequences and structural homology between Chikungunya virus (ChikV) E1 glycoprotein and human HLA-B27 molecule were identified. In addition, the peptides derived from ChikV glycoprotein E1 induced significant inflammation in C57BL/6J mice (19). Based on proteomic studies and sequence analysis, some evidence has also shown that Dengue Hemorrhagic Fever may be caused by molecular mimicry between different coagulation molecules with prM, E and NS1 viral proteins (20). Furthermore, it is already widely proposed that cross-recognition of common viral peptides with myelin antigens induces a molecular mimicry involved in MS development, especially in genetically susceptible individuals (15).
Zika fever is a self-limited disease, still, less than 5% of symptomatic patients may develop neurological manifestations (21,22). We evaluated 305 patients who had suspected infection with common arboviruses circulating in Brazil, of which 26 were positive for ZikV and, surprisingly, 4 patients had MS-like multifocal syndromes.
Patient 1 presented with headache, optical neuritis, and cervical myelitis associated to a cervical lesion (Figure 1 E) and asymptomatic multifocal brain lesions on MRI, one of which had gadolinium enhancement. This distribution of brain lesions, paired with positive oligoclonal bands (OCB) found on CSF analysis, resembles the pattern usually found in MS (Figure 1 A-D and Table 1). Although this patient developed these neurological manifestations five days after the first symptoms of viral infection, it was only possible to make the ZikV diagnosis after sixty days, thus explaining the IgM negativity in serum. Patient 2 had a diagnosis of acute flaccid paraplegia 11 days after a viral prodrome, and 3 months later developed tetraparesis associated with longitudinal extensive transverse myelitis (Figure 2 C and D), centrally located (Figure 2 C3, D3), with focal tapering of the cervical/dorsal transition on sagittal STIR (Figure 2 C1), resembling the extension and sequelae areas usually seen in NMOSD. Furthermore, the lesion had anterior horn involvement (Figure 2 D4). A recent case report identified concurrent GBS and ADEM in a 24-year-old woman who developed acute ZikV infection. The authors postulate this case was para-infectious, induced by neurotropism and activation of an immune response against ZikV (23). This same mechanism is probably involved in the development of this NMOSD phenotype in our patient. Patient 3 presented with tetra paresis and ataxia associated to brain lesions mainly affecting the brainstem on axial T2 images, including the posterior aspect of the mesencephalon (Figure 3 E), pons (Figure 3 F) and the medial cerebellar peduncle (Figure 3 G). Patient 4 presented with optic neuritis and multifocal myelitis with cervical and dorsal lesions, as usually found in a first manifestation of MS (Figure 4 A, B). This patient could be classified as having a clinical isolated syndrome (CIS) with high risk of conversion to MS due the distribution and number of T2 white matter lesions. Although the optical neuritis pattern resembles the one of NMOSD, the spinal cord lesions are MS-like.
Lucchese et al, 2016, observed that ZikV antigens are commonly involved in microcephaly and GBS. 129 immunopositive epitopes are reported as having peptide overlap with human proteins that may relate to demyelination and axonal neuropathies. This indicates that cross-reactivity with human proteins might contribute to the mechanisms linking ZikV infection to GBS (11). The IDD phenotype attributed to ZikV infection seems to mimic MS manifestations. Molecular mimicry is assessed in this study by investigating homologous regions between ZikV antigens and human MS autoantigens using bioinformatics tools. Sequence homology comparisons between NS5 ZikV and PLP MS protein revealed a homology of 5/6 consecutive amino acids CSSVPV/CSAVPV (Figure 5A). A study that performed antigenic B-cell epitopes prediction found an antigenic peptide from position 528 to 539 (NAICSSVPVDWV) of ZIKV NS5, which had the maximum residual score of 1.203 and might present a preliminary set of peptides for future vaccine development against ZIKV (24). Calculating the TM-score of NS5 ZIKV and PLP MS 3D structures demonstrated that both proteins are in almost the same fold, both are in alpha helix and they have topological similarity (Figure 5B) (25).
Interestingly, ZIKV African (MR766) lineage strain, revealed exactly the same Human PLP sequence (CSAVPV), and recombinant NS5 proteins from Africa and from Brazil revealed similar levels of RNA synthesis (26). It is already known that MR766 strain is more virulent and causes more severe brain damage than current Asian lineage and dengue virus (27). When inoculated subcutaneously in adult transgenic mice (knockout) C57BL/6 Stat2-/-, MR766 strain induces short episodes of severe neurological symptoms, followed by lethality. Furthermore, this strain was able to induce higher levels of inflammatory cytokines and markers associated with cellular infiltration into the brain of infected mice (28). Li et al, 2019, observed that MR766 strain and epidemic Brazilian (BR15 and ICD) ZIKV strains are different in viral attachment to host neuronal cells, viral permissiveness and replication, as well as in the induction of cytopathic effects (29).
Autoreactivity to PLP in patients with MS has been investigated in human and animal model by various groups worldwide (30). A recent study involving PLP’s Epitopes involved in MS, found CSAVPV (in PLP161–177 residues) among the most immunogenic regions of PLP (31). In addition, the crystal structure of the NS5 ZikV protein reveals a conserved domain conformation of Flaviviruses, a genus that includes a variety of human pathogens such as dengue virus, yellow fever virus, West Nile virus, Spondweni virus and the Japanese encephalitis virus (32). So, the presence of high identity between NS5 ZikV and PLP, an autoantigen widely implicated in the pathogenesis of MS (33), leads us to postulate that molecular mimicry may have a role in the development of inflammatory demyelinating damage, a hallmark of the IDD produced by this genus of virus.
Both genetic and environmental factors have been shown to contribute to the pathogenesis of autoimmune diseases. It is well-established that HLA-DR15 haplotype bears the strongest association to MS (34). In a Brazilian study, it was observed that the presence of HLA-DRB1*1501 allele confers an ethnicity-dependent MS susceptibility in Caucasian patients and that HLA-DQB1*0602 allele confers an ethnicity independent susceptibility (35). Using HLA class II transgenic (Tg) mice, several studies have demonstrated HLA-DR-dependent disease following immunization by MBP, PLP, or MOG (36,37). However, it was observed that HLA-DRB1*1501 Tg mice were refractory to disease induction by overlapping PLP peptides, while HLA-DQB1*0602 Tg mice were susceptible to disease induction by PLP139–151 and PLP175–194 peptides (38). It has been seen that Both PLP139–151 and PLP178–191 epitopes are key targets of T-cells, and are increased in MS patients versus healthy controls (39). However, this does not mean that PLP161–177 residues are not encephalitogenic-related, but that they need further animal and human model studies. Therefore, PLP autoimmunity and HLA haplotype have been strongly associated with lesion localization, as well as remission and relapse rates in MS (40).