Inhibition of type I interferon induction and signalling by mosquito-borne flaviviruses

Abstract

The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, flaviviruses have developed key strategies to counteract host immune defences, including the type I interferon response. They employ different mechanisms to control interferon signal transduction and effector pathways, and key research generated over the past couple of decades has uncovered new insights into their abilities to actively decrease interferon antiviral activity. Given the lack of antivirals or prophylactic treatments for many flaviviral infections, it is important to fully understand how these viruses affect cellular processes to influence pathogenesis and disease outcome. This review will discuss the strategies mosquito-borne flaviviruses have evolved to antagonise type I interferon mediated immune responses.

Keywords: Flavivirus; interferon antagonists; sfRNA; type I interferon.

Figure 1

(a) Organisation of the flavivirus genome. The flavivirus genome is composed of a single‐stranded, positive‐sense RNA, of approximately 11 kb. The single open reading frame contains the three structural proteins (C: capsid, prM: premembrane, E: envelope) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). These are flanked on either side by highly structured 5′ and 3′ untranslated regions. The gene products are generated from the single polyprotein by co‐ and posttranslational cleavage. This also results in the production of the 2K peptide between NS4A and NS4B. (b) Structure of ZIKV subgenomic flavivirus RNA (sfRNA), as predicted following structural studies and RNA folding analysis. Although the structure of sfRNA varies for different flaviviruses, they all contain similar motifs. All flavivirus sfRNAs contain stem loop (SL) and dumbbell (DBL) structures, which consist of conserved nucleotides capable of forming pseudoknots (PK). PK are represented by lines. Two sfRNAs of differing size are produced during ZIKV infection due to the stalling of XRN1 at the SL structures. Predicted sfRNAs: stalling at SL1 produces xrRNA1 (red box), and xrRNA2 (blue box) is produced by stalling at SL2 (Akiyama et al., 2016; Donald et al., 2016)