Zika virus-induced neuro-ocular pathology in immunocompetent mice correlates with anti-ganglioside autoantibodies

Abstract

A severe consequence of adult Zika virus (ZIKV) infection is Guillain-Barré Syndrome (GBS), where autoreactive antibodies attack peripheral and central nervous systems (CNS) resulting in neuro-ocular pathology and fatal complications. During virally induced GBS, autoimmune brain demyelination and macular degeneration correlate with low virus neutralization and elevated antibody-mediated infection among Fcγ-R bearing cells. The use of interferon-deficient mice for ZIKV studies limits elucidation of antibody-dependent enhancement (ADE) and long-term pathology (≥120 days), due to high lethality post-infection. Here we used immunocompetent BALB/c mice, which generate robust humoral immune responses, to investigate long-term impacts of ZIKV infection. A high infectious dose (1x10 6 FFU per mouse) of ZIKV was administered intravenously. Control animals received a single dose of anti-IFNAR blocking monoclonal antibody and succumbed to lethal neurological pathology within 13 days. Immunocompetent mice exhibited motor impairment such as arthralgia, as well as ocular inflammation resulting in retinal vascular damage, and corneal edema. This pathology persisted 100 days after infection with evidence of chronic inflammation in immune-privileged tissues, demyelination in the hippocampus and motor cortex regions of the brain, and retinal/corneal hyperplasia. Anti-inflammatory transcriptional responses were tissue-specific, likely contributing to differential pathology in these organs. Pathology in immunocompetent animals coincided with weakly neutralizing antibodies and increased ADE among ZIKV strains (PRVABC59, FLR, and MR766) and all Dengue virus (DENV) serotypes. These antibodies were autoreactive to GBS-associated gangliosides. This study highlights the importance of longevity studies in ZIKV infection and confirms the role of anti-ganglioside antibodies in ZIKV-induced neuro-ocular disease.

Pathogenesis and Manifestations of Zika Virus-Associated Ocular Diseases

“…This allows ZIKV access to cell types, such as neural stem cells (NSCs), neurons, astrocytes, and microglia [106]. The endothelial cells of the BBB and BRB cells can secrete matrix metalloproteinase-2 (MMP-2) and MMP-9 that are responsible for disrupting the impermeability function of BBB and BRB to facilitate access of infiltrating effector immune cells into the brain and retina, respectively [107]. ZIKV can cause a breakdown of the RPE impermeability function by impairing the intercellular junctions that link up the individual RPE cells that constitute the external BRB [105].…”

Emerging Infection, Vaccination, and Guillain–Barré Syndrome: A Review

“…As described earlier, anti-ganglioside antibodies are deeply involved in the pathogenesis of GBS [ 1 ]. A recent animal study demonstrated the production of IgG antibodies reactive to gangliosides, such as GD1a and GD1b, during Zika virus infection [ 34 ]. Another study showed increased levels of anti-ganglioside GD3 antibodies in sera obtained from patients infected with Zika virus with no neurological symptoms [ 35 ].…”

Exploring Zika Virus Impact on Endothelial Permeability: Insights into Transcytosis Mechanisms and Vascular Leakage

“…It also serves as a reservoir that promotes ZIKV’s spread throughout the BBB [ 39 ]. The BBB endothelial cells have the potential to release matrix metalloproteinase 2 (MMP-2), which is responsible for disrupting impermeability and making it easier for effector immune cells to enter the brain [ 97 ]. By affecting the intercellular connections that bind the individual brain cells and make up the external BBB, ZIKV can lead to a breakdown in the vascular impermeability function [ 98 ].…”