Departmental Bulletin Paper 〈Review〉Neuropathogenesis of Zika Virus Infection: Potential Roles of Antibody-Mediated Pathology

Tsunoda, Ikuo  ,  Omura, Seiichi  ,  Sato, Fumitaka  ,  Kusunoki, Susumu  ,  Fujita, Mitsugu  ,  Park, Ah-Mee  ,  Hasanovic, Faris  ,  Yanagihara, Richard  ,  Nagata, Satoshi

[Abstract] Zika virus(ZIKV) is an enveloped, positive-sense, single-stranded RNA virus that belongs to the genus Flavivirus, family Flaviviridae, which includes many human and animal pathogens, such as dengue virus (DENV),West Nile virus, and Japanese encephalitis virus. In the original as well as subsequent experimental and clinical reports, ZIKV seems to have moderate neurotropism (in animal models) and neurovirulence (in human fetuses), but no neuroinvasiveness (in human adults). Intrauterine ZIKV infection (viral pathology) has been linked to an increased incidence of microcephaly, while increased Guillain- Barre syndrome (GBS) following ZIKV infection is likely immune-mediated (immunopathology). Clinically, in ZIKV infection, antibodies against other flaviviruses, such as DENV, have been detected; these antibodies can cross-react with ZIKV without ZIKV neutralization. In theory, such non-neutralizing antibodies are generated at the expense of decreased production of neutralizing antibodies (“antigenic sin”),leading to poor viral clearance, while the non-neutralizing antibodies can also enhance viral replication in Fc receptor (FcR)-bearing cells via antibody-dependent enhancement (ADE). Here, we propose three potential roles of the antibody-mediated pathogenesis of ZIKV infection: 1) cross-reactive antibodies that recognize ZIKV and neural antigens cause GBS; 2) ZIKV-antibody complex is transported transplacentally via neonatal FcR (FcRn), resulting in fetal infection; and 3) ZIKV-antibody complex is taken up at peripheral nerve endings and transported to neurons in the central nervous system (CNS), by which the virus can enter the CNS without crossing the blood-brain barrier.

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