An update on enterovirus 71 infection and interferon type I response

Abstract

Enteroviruses are members of Pichornaviridae family consisting of human enterovirus group A, B, C, and D as well as nonhuman enteroviruses. Hand, foot, and mouth disease (HFMD) is a serious disease which is usually seen in the Asia-Pacific region in children. Enterovirus 71 and coxsackievirus A16 are two important viruses responsible for HFMD which are members of group A enterovirus. IFN α and β are two cytokines, which have a major activity in the innate immune system against viral infections. Most of the viruses have some weapons against these cytokines. EV71 has two main proteases called 2A and 3C, which are important for polyprotein processing and virus maturation. Several studies have indicated that they have a significant effect on different cellular pathways such as interferon production and signaling pathway. The aim of this study was to investigate the latest findings about the interaction of 2A and 3C protease of EV71 and IFN production/signaling pathway and their inhibitory effects on this pathway.

Keywords: 2A protease; 3C protease introduction; enterovirus 71; interferon type I.

Figure 1

IFN production pathway and different ways that the virus disrupts this pathway. Downregulation: long line with a small line at the end; scissor shape: cleavage by protease; IF production pathway activation was indicated in two ways. Left: Activation of pathway was indicated when ssRNA or dsRNA are in the cytoplasm, in which case two adaptors (RIG1 and MDA5) recognize them, resulting in activation of IPS1 (MAVS, VISA, or cardif). IPS activates two other adaptors (IKK and TBK1) leading to phosphorylation of IRF3 and IRF7. Translocation of these adaptors to the nucleus causes ISRE promoter activation and IFN production. 2A protease has inhibitory effects in this pathway with cleavage of MDA5 and IPS1, but 3C protease downregulates RIG1 through interaction. Right: Activation of pathway is observed when ssRNA or dsRNA are in the endosome. In this situation, TLR3 and TLR7/8 are responsible for RNA recognition, resulting in the activation of two adaptors (TRIF and MYD88). TRIF activates other adaptors such as TRAF3, IKK, and TBK1 giving rise to the activation of IRF7 and IRF3, where translocation of these proteins to the nucleus causes IFN production. MYD88 also activates some other adaptors including IRAK1, IRAK4, and TRAF6 leading to phosphorylation and activation of IRF7 and translocation to the nucleus. As can be seen, 3C protease affects this pathway by cleaving IRF7 and preventing its translocation to the nucleus

Figure 2

IFN signaling pathway and different ways that the virus interferes with this pathway. Downregulation: the long line with a small line at the end; inhibition of phosphorylation: the long line with a black circle at the end; scissor shape: cleavage by protease; EV71: enterovirus 71 infection. Attachment of IFN type 1 to IFNR1 and IFNR2 results in phosphorylation and activation of two adaptors called JNK1 and TYK2. The phosphorylation of these two proteins causes activation of STAT1 and STAT2 adaptors which form a complex with IRF9 and KPNA1, with the complex being called ISGF3. As can be seen in this image, STAT1 has a residue (a nuclear localization signal) which is recognized by KPNA1. This attachment induces translocation of ISGF3 to the nucleus and induces ISG's promoter. 2A protease can suppress the pathway by interacting with IFNR1, and 3C protease can cleave IRF9 and inhibit formation of ISGF3. EV71 infection can also inhibit phosphorylation of JNK1, TYK2, STAT1, and STAT2 which has been suggested in some studies. One of the latest reports found new mechanisms through which EV71 infection causes downregulation of KPNA1 in a caspase 3‐dependent manner and inhibits translocation of ISGF3 to nucleus