Neuropathogenesis of Zika Virus Infection : Potential Roles of Antibody-Mediated Pathology

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-Barré 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.

Keywords: Animal Models; Experimental Autoimmune Neuritis; Gangliosides; Placenta; Retrograde Axonal Flow; Theiler’s Murine En-cephalomyelitis Virus; Yellow Fever Virus.

Fig. 1

Zika Forest, located near Lake Victoria in Uganda. Zika virus (ZIKV) was first isolated from a sentinel monkey in Zika Forest in 1947.

Fig. 2

Neuropathology of West Nile virus (WNV) encephalitis. The brain was harvested from mice infected with WNV subcutaneously, and embedded in paraffin. (a) Meningitis (arrowheads) and perivascular cuffing (arrow) composed of mononuclear cells in the brain (Luxol fast blue stain). (b) T cells (arrows) in the perivascular cuffing by immunohistochemistry against CD3. (c, d) Viral antigens (arrows) in the cytoplasm and cell processes of neurons by immunohistochemistry with rabbit anti-WNV antibody (1 : 4,000 dilution, 81-015, BioReliance, Rockville, Maryland, USA), following trypsin treatment.

Fig. 3

Clearance or enhancement of viral infections mediated by anti-viral antibodies in the sequential viral infections, (a) In the primary infection with A-virus (e.g., dengue virus belonging to the genus Flavivirus), anti-A virus antibodies (Abs) are produced, resulting in viral neutralization and clearance. Here, a second infection with B-virus that is related to A-virus (e.g., Zika virus belonging to the genus Flavivirus) (b) or with irrelevant C-virus (e.g., picornavirus) (c) can occur, (c) C-virus infection induces only anti-C-virus Abs, but not anti-A-virus Ab, resulting in neutralization and clearance of the C-virus. (b) On the other hand, since B-virus mimics A-virus antigenically containing epitopes that are cross-reactive to A-virus, B-virus infection can induce higher Ab responses to A-virus than B-virus. Then, if increased anti-A-virus Abs neutralize B-virus, this results in efficient clearance of B-virus (“antigenic blessing”). On the contrary, if anti-A-virus Abs have no neutralizing activity to B-virus, decreased anti-B-virus Ab production at the expense of increased anti-A-virus Ab production results in poor clearance of B-virus (“antigenic sin”). Moreover, the Fc region of the virus-antibody complex can be captured by Fc receptor (FcR)-positive (+) cells, such as macrophages, leading to viral replication in FcR⁺ cells, which is termed “antibody-dependent enhancement of infection (ADE)”.

Fig. 4

Three hypothetical pathogenic roles of anti-Zika virus (ZIKV) antibody (Ab) in Guillain-Barré syndrome (GBS) and microcephaly, (a) Anti-ZIKV antibodies may cross-react with neural antigens specific to the peripheral nervous system (PNS), which damages PNS, leading to GBS. (b) Non-neutralizing IgG can form ZIKV-IgG immune complex, which can be captured by the neonatal Fc receptor (FcRn) on the placenta without viral neutralization. This will lead to transplacental passage of the immune complex, and infection of the fetus, causing microcephaly, (c) The immune complex, composed of ZIKV and non-neutralizing IgG antibody, is taken up at the nerve ending via Feγ receptor (FcγR) in the periphery, and then transported to the cell body of neurons in the central nervous system (CNS), using retrograde axonal flow. Here, by this neural route, the virus can enter the CNS without crossing the blood-brain barrier (BBB).