Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection

Megan M. Slough, Rong Li, Andrew S. Herbert, Gorka Lasso, Ana I. Kuehne, Stephanie R. Monticelli, Russell R. Bakken, Yanan Liu, Agnidipta Ghosh, Alicia M. Moreau, Xiankun Zeng, Félix A. Rey, Pablo Guardado-Calvo, Steven C. Almo, John M. Dye, Rohit K. Jangra (), Zhongde Wang () and Kartik Chandran ()
Additional contact information
Megan M. Slough: Albert Einstein College of Medicine
Rong Li: Utah State University
Andrew S. Herbert: United States Army Medical Research Institute of Infectious Diseases
Gorka Lasso: Albert Einstein College of Medicine
Ana I. Kuehne: United States Army Medical Research Institute of Infectious Diseases
Stephanie R. Monticelli: United States Army Medical Research Institute of Infectious Diseases
Russell R. Bakken: United States Army Medical Research Institute of Infectious Diseases
Yanan Liu: Utah State University
Agnidipta Ghosh: Albert Einstein College of Medicine
Alicia M. Moreau: United States Army Medical Research Institute of Infectious Diseases
Xiankun Zeng: United States Army Medical Research Institute of Infectious Diseases
Félix A. Rey: Université Paris Cité, CNRS UMR3569, Structural Virology Unit
Pablo Guardado-Calvo: Université Paris Cité, CNRS UMR3569, Structural Virology Unit
Steven C. Almo: Albert Einstein College of Medicine
John M. Dye: United States Army Medical Research Institute of Infectious Diseases
Rohit K. Jangra: Albert Einstein College of Medicine
Zhongde Wang: Utah State University
Kartik Chandran: Albert Einstein College of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Andes 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.

Date: 2023
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DOI: 10.1038/s41467-023-40126-y

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