[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
The neonatal Fc receptor is a pan-echovirus receptor
Stefanie Morosky, Alexandra I. Wells, Kathryn Lemon, Azia S. Evans, Sandra Schamus, Christopher J. Bakkenist, and Carolyn B. Coyne
PNAS published ahead of print February 11, 2019 / DOI: https://doi.org/10.1073/pnas.1817341116
Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved January 9, 2019 (received for review October 8, 2018)
Echoviruses are associated with aseptic meningitis and induce severe and sometimes fatal disease in neonates and young infants. Here, we identify the neonatal Fc receptor (FcRn) as a pan-echovirus receptor. FcRn is expressed on the surface of the human placenta, and throughout life on intestinal enterocytes, liver hepatocytes, and in the microvascular endothelial cells that line the blood–brain barrier. This pattern of expression is consistent with the organ sites targeted by echoviruses in humans, as the primary entry site of infection is the intestinal and secondary sites of infection include the liver and brain. These findings provide important insights into echovirus pathogenesis and may explain the enhanced susceptibility of neonates to echovirus-induced disease.
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.
echovirus – neonatal Fc receptor – enterovirus – virus receptor – FcRn
1 S.M. and A.I.W. contributed equally to this work.
2 To whom correspondence should be addressed. Email: firstname.lastname@example.org.
Author contributions: A.I.W., K.L., C.J.B., and C.B.C. designed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. performed research; S.M., A.I.W., K.L., A.S.E., S.S., C.J.B., and C.B.C. analyzed data; and S.M., A.I.W., A.S.E., C.J.B., and C.B.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1817341116/-/DCSupplemental.
Published under the PNAS license.
Keywords: Enterovirus; Echovirus; Pediatrics.