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

Megan M Slough (1) , Rong Li (2) , Andrew S Herbert (3) , Gorka Lasso (1) , Ana I Kuehne (3) , Stephanie R Monticelli (3) , Russell R Bakken (3) , Yanan Liu (2) , Agnidipta Ghosh (1) , Alicia M Moreau (3) , Xiankun Zeng (3) , Félix A Rey (4) , Pablo Guardado-Calvo (4, 5) , Steven C Almo (1) , John M Dye (3) , Rohit K Jangra (1) , Zhongde Wang (2) , Kartik Chandran (1)

1 Albert Einstein College of Medicine [New York]
2 USU - Utah State University
3 USAMRIID - U.S. Army Medical Research Institute of Infectious Diseases
4 Virologie Structurale - Structural Virology
5 Biologie structurale des maladies infectieuses / Structural biology of infectious diseases

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.

Domaines: Sciences du Vivant [q-bio]; Virologie

Megan M Slough, Rong Li, Andrew S Herbert, Gorka Lasso, Ana I Kuehne, et al.. Two point mutations in protocadherin-1 disrupt hantavirus recognition and afford protection against lethal infection. Nature Communications, 2023, 14 (1), pp.4454. ⟨10.1038/s41467-023-40126-y⟩. ⟨pasteur-04364167⟩