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

• Published in: Nature communications Vol. 14; no. 1; p. 4454
• Main Authors: Slough, Megan M., Li, Rong, Herbert, Andrew S., Lasso, Gorka, Kuehne, Ana I., Monticelli, Stephanie R., Bakken, Russell R., Liu, Yanan, Ghosh, Agnidipta, Moreau, Alicia M., Zeng, Xiankun, Rey, Félix A., Guardado-Calvo, Pablo, Almo, Steven C., Dye, John M., Jangra, Rohit K., Wang, Zhongde, Chandran, Kartik
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-07-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14/63; 38/70; 45/41; 631/1647/334/1874/1535; 631/326/596/2557; 631/326/596/2564; 82/83; Amino acids; Animals; Binding sites; Cadherins; Communicable Diseases; Cricetinae; Glycoproteins; Hamsters; Hantavirus; Humanities and Social Sciences; Life Sciences; Lung diseases; Mesocricetus; Microbiology and Parasitology; multidisciplinary; Mutation; Orthohantavirus; Point Mutation; Protocadherin; Protocadherins; Residues; RNA Viruses; Science; Science (multidisciplinary); Syndrome; Virology; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40126-y

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.
Protocadherin-1 (PCDH1) is a critical host factor for hantaviruses that can cause severe cardiopulmonary syndrome. Here, the authors map the binding site of the viral glycoprotein complex within PCDH1 and show that mutations engineered at this site can protect Syrian hamsters from viral challenge.