Abstract
Neonatal echovirus infections are characterized by severe hepatitis and neurological complications that can be fatal. Here, we show that expression of the human homologue of the neonatal Fc receptor (hFcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are key host determinants involved in echovirus pathogenesis. We show that expression of hFcRn alone is insufficient to confer susceptibility to echovirus infections in mice. However, expression of hFcRn in mice deficient in type I interferon (IFN) signaling, hFcRn-IFNAR-/-, recapitulate the echovirus pathogenesis observed in humans. Luminex-based multianalyte profiling from E11 infected hFcRn-IFNAR-/- mice revealed a robust systemic immune response to infection, including the induction of type I IFNs. Furthermore, similar to the severe hepatitis observed in humans, E11 infection in hFcRn-IFNAR-/- mice caused profound liver damage. Our findings define the host factors involved in echovirus pathogenesis and establish in vivo models that recapitulate echovirus disease in humans.
Highlights
Echoviruses are small (~30 nm) single-stranded RNA viruses that belong to the Picornaviridae family
Because many enteroviruses are restricted by type I IFN signaling in small animal models and because we have previously shown that Echovirus 11 (E11) is sensitive to recombinant IFN-β treatment [24], we reasoned that type I IFNs might play a key role in restricting E11 infection in vivo
In contrast to animals expressing human FcRn (hFcRn) or lacking IFNAR expression alone, we found that hFcRnTg32-IFNAR-/- suckling mice were highly permissive to E11 infection, with high levels of infectious virus circulating in blood (17 of 18 animals, Fig 1A)
Summary
Echoviruses are small (~30 nm) single-stranded RNA viruses that belong to the Picornaviridae family. Infants and neonates are often most severely impacted by echovirus infections, with the majority of enterovirus infections in infants below the age of two months caused by echoviruses [1,2]. Echovirus infections are devastating in Neonatal Intensive Care Unit (NICU) outbreaks, where they account for 15–30% of nosocomial viral infections and can result in death of the neonate in as many as 25% of cases [3,4,5,6]. Echovirus 11 (E11) is one of the most common serotypes associated with outbreaks in NICUs across the world [7,8]. Despite the severe clinical outcomes associated with echovirus infections, the tissue tropism and pathogenesis of infection remain largely unknown due to the lack of established animal models to study E11 infection at secondary sites of infection, such as the liver and brain
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