ZIKV Strains Elicit Different Inflammatory and Anti-Viral Responses in Microglia Cells

Abstract

In recent years, the Zika Virus (ZIKV) has caused pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZS). Although all strains associated with worldwide outbreaks derive from the Asian lineage, the reasons for their enhanced spread and severity are not fully understood. In this study, we conducted a comparative analysis of miRNAs (miRNA-155/146a/124) and their cellular targets (SOCS1/3, SHP1, TRAF6, IRAK1), as well as pro- and anti-inflammatory and anti-viral cytokines (IL-6, TNF-α, IFN-γ, IL-10, and IFN-β) and peroxisome proliferator-activated receptor γ (PPAR-γ) expression in BV2 microglia cells infected with ZIKV strains derived from African and Asian lineages (ZIKVMR766 and ZIKVPE243). BV2 cells were susceptible to both ZIKV strains, and showed discrete levels of viral replication, with delayed release of viral particles without inducing significant cytopathogenic effects. However, the ZIKVMR766 strain showed higher infectivity and replicative capacity, inducing a higher expression of microglial activation markers than the ZIKVPE243 strain. Moreover, infection with the ZIKVMR766 strain promoted both a higher inflammatory response and a lower expression of anti-viral factors compared to the ZIKVPE243 strain. Remarkably, the ZIKKPE243 strain induced significantly higher levels of the anti-inflammatory nuclear receptor—PPAR-γ. These findings improve our understanding of ZIKV-mediated modulation of inflammatory and anti-viral innate immune responses and open a new avenue to explore underlining mechanisms involved in the pathogenesis of ZIKV-associated diseases.

Strain Variation Can Significantly Modulate the miRNA Response to Zika Virus Infection

“…Remarkably, while extensive differences were seen at the level of the miRNA, the strain type-specific effects were also seen at the protein level of a selected putative target, HSP70. The results from this study and others [69,71,72,76] indicate that future studies on the modulation of miRNAs as a consequence of ZIKV infection must take into account strain type variation, as the results generated by a single strain will be of limited value in understanding the role of miRNAs in ZIKV infection.…”

“…A number of studies have previously investigated the involvement of miRNAs in ZIKV infection [24,[62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]. These studies have variously identified the regulation of miR-302b, miR-302c, miR-194 and miR-30c in ZIKV-infected human NPCs in vitro [73], miR-146a in ZIKV-infected human microglial cells [75], hsa-miR-101-3p in ZIKV-infected human brain microvascular endothelial cells [67], mir-204 in human fetal neural stem cells as a consequence of ZIKV E protein expression [66], miR-7013-5p in ZIKV-infected fetal mouse neurons [62], miR-9 in ZIKV-infected mice [24] and miR-30e-3p, miR-30e-5p and miR-17-5p in ZIKV-infected astrocytes [70].…”

“…Nearly all miRNAs examined showed statistically significant differences between the two strains used (MU1-2017 and SV0010/15). Several other studies have examined alterations in miRNA expression as a consequence of different ZIKV strains [69,71,72,74,76]. Strikingly, all of these studies compared the original African-lineage Ugandan isolate of ZIKV (MR766) to a more recent Asian-lineage ZIKV [69,71,72,74,76].…”

“…Several other studies have examined alterations in miRNA expression as a consequence of different ZIKV strains [69,71,72,74,76]. Strikingly, all of these studies compared the original African-lineage Ugandan isolate of ZIKV (MR766) to a more recent Asian-lineage ZIKV [69,71,72,74,76]. Four of the studies reported at least some strain type variation in miRNA expression between the two isolates [69,71,72,76], while one study used two isolates but apparently did not compare expression across the isolates [74].…”

A review on Zika vaccine development

“…For pregnant women, most ZIKV infections are asymptomatic; however, mother-to-child transmission of the virus may result in severe fetal and childhood defects such as microcephaly, lissencephaly, cortical calcifications, uveitis, and unilateral acute maculopathy. For adults, ZIKV infection may cause Guillain–Barré syndrome (GBS) (Oliveira et al 2023 , Olmo et al 2023 ). Moreover, the viral RNA encodes a polypeptide precursor, and its amino terminus 1/3 produces three structural proteins, which are present in the envelope (E), premembrane/membrane (prM/M), and capsid (C) of the virion.…”