Type I Interferons Triggered through the Toll-Like Receptor 3–TRIF Pathway Control Coxsackievirus A16 Infection in Young Mice

Abstract

Coxsackievirus A16 (CVA16) is one of the major etiological agents of hand, foot, and mouth disease (HFMD) in children. The host defense mechanisms against CVA16 infection remain almost entirely unknown. Unlike previous observations with enterovirus 71 (EV71) infection, here we show that gamma interferon (IFN-␥) or invariant NK T cell deficiency does not affect disease development or the survival of CVA16-infected mice. In contrast, type I interferon receptor deficiency resulted in the development of more severe disease in mice, and the mice had a lower survival rate than wild-type mice. Similarly, a deficiency of Tolllike receptor 3 (TLR3) and TRIF, but not other pattern recognition receptors, led to the decreased survival of CVA16-infected mice. TLR3-TRIF signaling was indispensable for the induction of type I interferons during CVA16 infection in mice and protected young mice from disease caused by the infection. In particular, TRIF-mediated immunity was critical for preventing CVA16 replication in the neuronal system before disease occurred. IFN-␤ treatment was also found to compensate for TRIF deficiency in mice and decreased the disease severity in and mortality of CVA16-infected mice. Altogether, type I interferons induced by TLR3-TRIF signaling mediate protective immunity against CVA16 infection. These findings may shed light on therapeutic strategies to combat HFMD caused by CVA16 infection. IMPORTANCEHand, foot, and mouth disease (HFMD) is a major threat to public health in the Asia-Pacific region. Both CVA16 and EV71 are major pathogens that are responsible for HFMD. The majority of research efforts have focused on the more virulent EV71, but little has been done with CVA16. Thus far, host immune responses to CVA16 infection have not yet been elucidated. The present study discovered an initial molecular mechanism underlying host protective immunity against CVA16 infection, providing the first explanation for why CVA16 and EV71 cause different clinical outcomes upon infection of humans. Therefore, different therapeutic strategies should be developed to treat HFMD cases caused by these two viruses.

ATP1B3 cooperates with BST‐2 to promote hepatitis B virus restriction

“…Indeed, IFNs have been demonstrated to be effective against infection caused by many viruses, such as influenza A virus, 36,37 hepatitis C virus, 38 and coxsackievirus A16. 25 Hence, the specificity of ATP1B3 antivirus function needs to be investigated in the future.…”

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance

“…IFNAR1 knockout mice (33) and C57BL/6 mice were fed ad libitum under 12/12-h light/dark cycle in specific pathogenfree facility. Three-month-old mice were randomized into chow diet group (CD group) and high-salt diet group (HSD group).…”

microRNA expression profiling in human diploid cells infected with enterovirus 71 or coxsackievirus A16

“…The immunologic antiviral mechanisms induced by EV71 and CA16 infections were previously reported to be distinct in terms of the interferon (IFN) response [15,16]. In addition, in our previous studies, we observed an elevated expression of T-helper 2 (Th2) or Th1 cytokines in patients with EV71 or CA16 infection, respectively [17].…”

“…Most previous studies have typically focused on analysis of the pathological and immunological responses resulting from EV71 or CA16 infection [10,41,43]. Leng and colleagues reported that EV71 infection activates the immune response via natural killer T-cells but that CA16 activates the immune response via type I IFN [15,16]. However, the data comparing the differences between these two viral infections in detail are scarce.…”