Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
Center for Microbial Pathogenesis, University of Pittsburgh Medical Center (UPMC) Children's Hospital of Pittsburgh, Pittsburgh, PA 15224.
Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3758-3763. doi: 10.1073/pnas.1817341116. Epub 2019 Feb 11.
Echoviruses are amongst the most common causative agents of aseptic meningitis worldwide and are particularly devastating in the neonatal population, where they are associated with severe hepatitis, neurological disease, including meningitis and encephalitis, and even death. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. We show that loss of expression of FcRn or its binding partner beta 2 microglobulin (β2M) renders cells resistant to infection by a panel of echoviruses at the stage of virus attachment, and that a blocking antibody to β2M inhibits echovirus infection in cell lines and in primary human intestinal epithelial cells. We also show that expression of human, but not mouse, FcRn renders nonpermissive human and mouse cells sensitive to echovirus infection and that the extracellular domain of human FcRn directly binds echovirus particles and neutralizes infection. Lastly, we show that neonatal mice expressing human FcRn are more susceptible to echovirus infection by the enteral route. Our findings thus identify FcRn as a pan-echovirus receptor, which may explain the enhanced susceptibility of neonates to echovirus infections.
肠道病毒是全世界无菌性脑膜炎的最常见病因之一，在新生儿中尤其具有破坏性，可导致严重肝炎、包括脑膜炎和脑炎在内的神经疾病，甚至死亡。在这里，我们确定了新生儿 Fc 受体（FcRn）是一种泛肠道病毒受体。我们表明，FcRn 或其结合伴侣β2 微球蛋白（β2M）的表达缺失使细胞在病毒附着阶段对一系列肠道病毒感染具有抗性，并且针对β2M 的阻断抗体可抑制细胞系和原代人肠上皮细胞中的肠道病毒感染。我们还表明，人 FcRn 的表达使非允许的人源和鼠源细胞对肠道病毒感染敏感，并且人 FcRn 的细胞外结构域可直接结合肠道病毒颗粒并中和感染。最后，我们表明表达人 FcRn 的新生小鼠通过肠内途径更容易感染肠道病毒。因此，我们的发现确定了 FcRn 是一种泛肠道病毒受体，这可能解释了新生儿对肠道病毒感染的易感性增强。
