Zika Virus Pathogenesis: A Battle for Immune Evasion

Abstract

Zika virus (ZIKV) infection and its associated congenital and other neurological disorders, particularly microcephaly and other fetal developmental abnormalities, constitute a World Health Organization (WHO) Zika Virus Research Agenda within the WHO's R&D Blueprint for Action to Prevent Epidemics, and continue to be a Public Health Emergency of International Concern (PHEIC) today. ZIKV pathogenicity is initiated by viral infection and propagation across multiple placental and fetal tissue barriers, and is critically strengthened by subverting host immunity. ZIKV immune evasion involves viral non-structural proteins, genomic and non-coding RNA and microRNA (miRNA) to modulate interferon (IFN) signaling and production, interfering with intracellular signal pathways and autophagy, and promoting cellular environment changes together with secretion of cellular components to escape innate and adaptive immunity and further infect privileged immune organs/tissues such as the placenta and eyes. This review includes a description of recent advances in the understanding of the mechanisms underlying ZIKV immune modulation and evasion that strongly condition viral pathogenesis, which would certainly contribute to the development of anti-ZIKV strategies, drugs, and vaccines.

Keywords: Zika virus (ZIKV); congenital and neurological disorders; immune evasion; infection; tissue propagation.

Figure 1

Schematic overview of the Zika virus (ZIKV) genome. The ZIKV genome is a single-stranded positive-sense RNA (+ssRNA) of approximately 11 Kb and codes a polyprotein which is cleaved in the endoplasmic reticulum (ER) lumen by the host and/or viral proteases to release three structural proteins (C, PrM and E; red boxes) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5; yellow boxes). The 5′ untranslated region (UTR) is susceptible for specific double methylation (represented in grey box at left) by the viral C-terminal methyltransferase domain of NS5 to behave like messenger RNA (mRNA) and hijacks host factors for translation and for masking the viral RNA to prevent cellular recognition and degradation. UTR loops at 3′ end are subgenomic flavivirus RNAs (sfRNAs) (shown in the grey box on the right), that play a role in the immune response evasion (see Section 2.4 in the main text).

Figure 2

Schematic overview of ZIKV NS proteins and sfRNAs as modulators of antiviral interferon (IFN) and associated signals. This diagram shows the interactions of cellular factors (green boxes) involved in the IFN pathway with the NS viral proteins (yellow boxes) and sfRNAs (sfRNA1 and 2) (orange box) that play a role in this IFN pathway. Color code inbox is indicated top left.