Defining the Role of the Neonatal Fc Receptor in a Novel Model of Echovirus II Infection

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PROJECT SUMMARY Enteroviruses are a significant growing public health concern. Enteroviruses, such as poliovirus, coxsackievirus B (CVB), echoviruses and enterovirus 71 (EV71), typically cause minor symptoms. However, neonates and children are particularly susceptible to severe enterovirus infections, which are characterized by neurological complications such as encephalitis, meningitis, and paralysis. In addition, neonatal infections of echovirus 11 (E11) result in liver failure, which lead to death of the neonate. These single-stranded RNA viruses are primarily transmitted through the fecal-oral route, targeting the gastrointestinal (GI) tract. After replication in the GI epithelium, these viruses disseminate into secondary target tissues such as the brain, pancreas, and liver. Many enteroviruses lack comprehensive mouse models that would allow a better understanding of pathogenesis in animals. Therefore, it is necessary to develop additional mouse models that accurately mimic the complexity of interactions in the GI epithelium as well as establishing more complete mouse models for certain enteroviruses to study pathogenesis at secondary sites of infection. Currently, only a few mouse models of E11 infection exist but they do not model infection at secondary sites such as the liver. In previous studies, we have identified a pan-echovirus receptor, the neonatal Fc receptor (FcRn). We showed that human transgenic neonatal mice expressing FcRn (hFcRnTg) were more susceptible to oral echovirus 11 (E11) infection. I have established an adult mouse model of disease where E11 infects the liver, a key site in human infection. I hypothesize that after dissemination from the GI tract, E11 infects Kupffer Cells (KCs) in the liver in an FcRn-dependent manner, resulting in tissue damage to the liver. Here, I seek to determine the cell tropism of E11 in the liver. I will use in vitro and in vivo models to elucidate these tropisms in the liver. Mouse models using hFcRnTg, mFcRn (WT), and FcRn-/- animals will be used to understand the cellular tropism and the role of FcRn in infection. Additionally, I want to understand how this cellular tropism influences functionality of the liver. In this aim, I will assess whether infection can mediate cell death in the liver and whether liver enzymes are elevated during infection, suggesting liver dysfunction. In addition, I seek to appreciate the innate immune response to E11 in the liver. I will use mouse models that are deficient in type I or III interferon signaling to assess the role of IFNs in E11 infection of the liver. These proposed studies will be one of the first to define the cellular tropism and the antiviral response to E11 infection in a secondary site of infection such as the liver.