Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection
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Published:2023-07-24
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Slough Megan M.ORCID, Li Rong, Herbert Andrew S., Lasso Gorka, Kuehne Ana I., Monticelli Stephanie R., Bakken Russell R., Liu Yanan, Ghosh Agnidipta, Moreau Alicia M., Zeng XiankunORCID, Rey Félix A.ORCID, Guardado-Calvo PabloORCID, Almo Steven C., Dye John M., Jangra Rohit K.ORCID, Wang ZhongdeORCID, Chandran KartikORCID
Abstract
AbstractAndes virus (ANDV) and Sin Nombre virus (SNV) are the etiologic agents of severe hantavirus cardiopulmonary syndrome (HCPS) in the Americas for which no FDA-approved countermeasures are available. Protocadherin-1 (PCDH1), a cadherin-superfamily protein recently identified as a critical host factor for ANDV and SNV, represents a new antiviral target; however, its precise role remains to be elucidated. Here, we use computational and experimental approaches to delineate the binding surface of the hantavirus glycoprotein complex on PCDH1’s first extracellular cadherin repeat domain. Strikingly, a single amino acid residue in this PCDH1 surface influences the host species-specificity of SNV glycoprotein-PCDH1 interaction and cell entry. Mutation of this and a neighboring residue substantially protects Syrian hamsters from pulmonary disease and death caused by ANDV. We conclude that PCDH1 is a bona fide entry receptor for ANDV and SNV whose direct interaction with hantavirus glycoproteins could be targeted to develop new interventions against HCPS.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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