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.

An in vivo model of echovirus-induced meningitis in neonates

“…Consistent with our previous findings with E11 (21), we found that there was robust replication in the livers and pancreases of E5 infected hFcRn Tg32 -IFNAR -/mice (12 of 12 mice) (Supplemental Figure 1C, 1D). However, in contrast to the brain, we found that hFcRn Tg32 -IFNLR -/animals also contained virus in the liver (4 of 8 mice) and pancreas (8 of 8 mice) (Supplemental Figure 1C, 1D).…”

“…We also detected low to mid-levels of E5 in the pancreases of immunocompetent hFcRn Tg32 mice (5 of 5 mice) and to a much lesser extent in liver (1 of 5 mice) (Supplemental Figure 1C, 1D). There was no detectable virus in any animals expressing the murine homologue of FcRn (Supplemental Figure 1C, 1D), consistent with our previous work (21). Collectively, these data show that echovirus infections in the brain require expression of hFcRn and that the primary barrier to infection is type I IFN-mediated signaling.…”

“…028288) mice were purchased from The Jackson Laboratory. hFcRn Tg32 -IFNAR -/mice were generated as described previously (21). B6.Ifnlr -/-/J (IFNLR -/-) mice were provided by Dr. Megan Baldridge (Washington University School of Medicine).…”

“…Previously, we developed a mouse model of echovirus pathogenesis through intraperitoneal (IP) inoculation using mice expressing the human homologue of hFcRn (hFcRn Tg32 ) that are also ablated in type I IFN signaling by deletion of IFNAR (hFcRn Tg32 -IFNAR -/-) (21). hFcRn Tg32 mice are deficient in expression of mouse FcRn and express human FcRn under the control of the native human promotor (29).…”

“…Other work suggests that type I interferons (IFNs) play a role in echovirus 11 CNS disease following intracranial inoculation (20). We previously generated an in vivo mouse model of echovirus 11 pathogenesis using adult and neonatal mice and showed that expression of the human homologue of FcRn in mice lacking type I IFN signaling were susceptible to echovirus infection, including infection of the brain (21). However, the consequences of echovirus infection including the induction of cytokines and cell death in the brains of these mice, as well as identification of the region(s) of the brain targeted by infection were not explored.…”