A battle between host and pathogen : the innate immune response and enterovirus evasion strategies

Abstract: Infections with Coxsackieviruses are common and in most cases the infection is asymptomatic and efficiently cleared. On rare occasions, however, an infection can lead to severe diseases including myocarditis, hepatitis and pancreatitis. Infections with Coxsackieviruses have also been implicated in the pathogenesis of type 1 diabetes (T1D). Upon a virus infection, the innate immune response plays an important role in restricting viral replication and further dissemination to susceptible organs. An inability to mount an appropriate immune response may increase virus-induced damage. This thesis focuses on the cross-talk between host and Coxsackievirus. The aims were to identify mechanisms by which the host restricts infection and to unravel strategies used by the virus to evade the host immune response. We identified that the intracellular virus receptor melanoma differentiation associated factor 5 (MDA5) has an important role in the host response to a Coxsackievirus infection. Absence of this receptor led to a decreased ability to control viral replication, which resulted in severe tissue damage and increased mortality. Polymorphisms in interferon induced with helicase C domain (IFIH1), the gene encoding MDA5, regulate the risk for T1D development, further implicating the involvement of Coxsackieviruses in T1D pathogenesis. Studies in this thesis showed that the Ala946Thr polymorphism in IFIH1 regulates how human pancreatic islets respond to a Coxsackievirus infection. The predisposing allele 946Thr was associated with lower induction of interferons (IFNs) and IFN-inducible genes. It has previously been shown that type I IFNs play an important role in the host defense against Coxsackievirus. Type III IFNs are a recently described group of IFNs that mainly act on epithelial cells and provides protection against virus infection. This thesis established a novel role for the type III IFNs in inducing an antiviral state in infected human pancreatic islets. Moreover, it demonstrated that type III IFNs protect primary human cells, inlcuding pancreatic islets and hepatocytes, from a Coxsackievirus infection. Due to the potent antiviral effect of IFNs, most viruses have developed mechanisms to inhibit their actions. In this thesis, strategies utilized by Coxsackieviruses to inhibit the induction of type III IFN were identified, which further underlines the importance of this group of IFNs in controlling a Coxsackievirus infection. The findings presented in this thesis further our understanding of how the host recognizes and combats a Coxsackievirus infection, and also describe evasion strategies used by the virus to inhibit these protective mechanisms. The studies also demonstrate that a polymorphism in IFIH1 affects the ability of human pancreatic islets to respond to a Coxsackievirus infection. A better understanding of the host-pathogen interactions may help in the development of therapeutic strategies to reduce the severity of Coxsackievirus infections.