Guillain-Barré syndrome following Zika virus infection is associated with a diverse spectrum of peripheral nerve reactive antibodies

IntroductionRecent outbreaks of Zika virus (ZIKV) in South and Central America have highlighted significant neurological side effects. Concurrence with the inflammatory neuropathy Guillain-Barré syndrome (GBS) is observed in 1:4000 ZIKV cases. Whether the neurological symptoms of ZIKV infection are a consequence of autoimmunity or direct neurotoxicity is unclear.MethodsWe employed rat dorsal root ganglion (DRG) neurons, Schwann cells (SCs), and human stem cell-derived sensory neurons myelinated with rat SCs as cellular models to screen for IgG and IgM autoantibodies reactive to peripheral nerve in sera of ZIKV patients with and without GBS. In this study, 52 ZIKV-GBS patients were compared with 134 ZIKV-infected patients, and 91 non-ZIKV controls. Positive sera were taken forward for target identification by immunoprecipitation and mass spectrometry, and candidate antigens validated by ELISA and cell-based assays. Autoantibody reactions against glycolipid antigens were also screened on an array.ResultsOverall, IgG antibody reactivity to rat SCs (6.5%) and myelinated co-cultures (9.6%) were significantly higher, albeit infrequently, in the ZIKV-GBS group compared to all controls. IgM antibody immunoreactivity to DRGs (32.3%) and SCs (19.4%) was more frequently observed in the ZIKV-GBS group compared to other controls, while IgM reactivity to co-cultures was as common in ZIKV and non-ZIKV sera. Strong axonal-binding ZIKV-GBS serum IgG antibodies from one patient were confirmed to react with neurofascin-155 and 186. Serum from a ZIKV non-GBS patient displayed strong myelin-binding and anti-lipid antigen reaction characteristics. There was no significant association of ZIKV-GBS with any anti-glycolipid antibodies.ConclusionAutoantibodies in ZIKV associated GBS patients’ sera target heterogeneous peripheral nerve antigens suggesting heterogeneity of the humoral immune response despite a common prodromal infection.