Human FcRn expression and Type I Interferon signaling control Echovirus 11 pathogenesis in mice

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.

Enterovirus replication and dissemination are differentially controlled by type I and III interferons in the GI tract

“…There were no significant differences in titers between male and female mice, although male mice did have overall higher titers in the liver (Supplemental Figure 1B). These data are consistent with our previous work data showing that hFcRn Tg32 -IFNAR -/pups or adult mice inoculated by the IP route have high levels of echovirus infections in the liver and pancreas 21 .…”

“…The selective induction of type III IFNs in murine-derived enteroids suggests that these IFNs are key mediators in the control of echovirus infections in the intestinal epithelium. To test this, we derived enteroids from small intestine tissue of mice expressing hFcRn that are deficient in IFNAR expression (hFcRn Tg32 -IFNAR -/- ) 21 . To perform parallel studies in enteroids deficient in type III IFN signaling, we crossed hFcRn Tg32 mice to mice deficient in IFNLR expression (hFcRn Tg32 -IFNLR -/- ).…”

“…To do this, we performed hybridization chain reaction (HCR), which allows for multiplexed fluorescent quantitative RNA detection with enhanced sensitivity over conventional hybridization approaches 24,25 . Our previous work using this method showed that echoviruses exclusively target hepatocytes following IP inoculation 21 .…”

“…We and others previously identified the human neonatal Fc receptor (hFcRn) as a primary receptor for echoviruses 19,20 . In contrast, mouse FcRn does not function as an echovirus receptor and does not support replication in vivo 19,21 . FcRn is expressed at the apical membrane of polarized enterocytes, where it binds to IgG and albumin, is internalized by endocytosis, and delivers its cargo to early and late endosomes, with the eventual release of IgG and albumin into the interstitium 22 .…”

“…FcRn is expressed at the apical membrane of polarized enterocytes, where it binds to IgG and albumin, is internalized by endocytosis, and delivers its cargo to early and late endosomes, with the eventual release of IgG and albumin into the interstitium 22 . However, expression of hFcRn alone is not sufficient for echovirus infection in adult or neonatal mice and ablation of IFNAR in hFcRn-expressing mice is required for infection following intraperitoneal (IP) inoculation 21 . However, the roles of hFcRn and IFN signaling following inoculation via the enteral route was not explored.…”