Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Abstract

Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3C pro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3C pro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3C pro proteins all cleave transforming growth factor ␤-activated kinase 1 (TAK1), resulting in the inhibition of NF-B activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3C pro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3C pro proteins block MDA5-triggered type I IFN induction. The 3C pro proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3C pro proteins cleave TAK1 to inhibit the NF-B response. Thus, our data demonstrate that circulating HFMDassociated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3C pro proteins as an antiviral strategy.KEYWORDS MDA5, TAK1, MAVS, 3C protease, CV-A16, CV-A6, EV-D68, HFMD, innate immune response

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

“…The present model might therefore provide evidence that IFN signaling deficiency is a factor in susceptibility to this type of infection. The basis for any possible IFN deficiency in asthma is less certain, but differences based on the type of infection might be highly relevant given the varying capacity of different viruses to subvert IFN production and signaling, including EV-D68 and SeV (25,26,75). In that context, the results provide the intriguing possibility that EV-D68, similar to SeV and IAV, might be particularly prone to cause the severity of acute infection that leads to chronic disease.…”

“…In concert with shared viral features, EV-D68 can also cause respiratory infection, and this infection can result in severe illness in susceptible populations, particularly asthmatics (18-23) as well as acute flaccid myelitis in other patients, based possibly on neuronal receptor binding (24). The severity of EV-D68-driven illness might be based on the viral capacity to subvert the IFN-based immune response (25,26), raising the possibility that any further IFN deficiency might no longer influence the infection. In addition, to our knowledge, EV-D68 infection is limited to an acute illness.…”

RNA‐virus proteases counteracting host innate immunity

“…A) . Recently, the CV‐A16, CV‐A6, and EV‐D68 3C pro s have also been shown to process TAK1 . In summary, the enterovirus 3C pro impairs NF‐κB activation.…”

“…Furthermore, Rui et al . detected by co‐IP that the CV‐A16, CV‐A6, or EV‐D68 3C pro s can also bind MDA5, thus disrupting the MDA5–MAVS interaction. Interestingly, these 3C pro s do not digest MDA5 and a proteolytically inactive, mutated 3C pro can also prevent MDA5 from activating IFN.…”

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

“…There are many other benefits that may arise by increased translation. Picornaviruses, including EV-D68, have been show to utilize their encoded proteases to manipulate the host-cell immune function [85,86]. Increased translation efficiency and the generation of more of these proteases could allow for a more robust immune evasion.…”