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The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDhI could provide strategies to reduce infection and disease caused by New World hantaviruses.
Hantaviruses systemically infect and replicate in endothelial cells, and the nonlytic dysregulation of these cells is thought to underlie the changes in vascular permeability that are a hallmark of the viral disease in humans2,9. avß3 integrins have been identified as in vitro determinants of hantavirus infection10, and viral subversion of ß3-integrin signalling in endothelial cells has been proposed to compromise vascular integrity9,10. Gene-complementation experiments have yielded other receptor candidates, including ß2 integrin11 and numerous components of the complement system12,13. However, the roles of these host factors in animal models of HPS or in humans remain undefined. Therefore, the identities of host molecules that mediate hantavirus infection in vivo and influence pathogenesis so far remain unknown.
To systematically uncover host factors for hantavirus entry, we14 and others15 previously used a recombinant vesicular stomatitis virus bearing the ANDV Gn/Gc glycoproteins (rVSV-ANDV Gn/Gc) to perform a loss-of-function genetic screen in HAP1 haploid human cells (Extended Data Fig. 1a). These screens identified several genes involved in the sterol regulatory element binding protein (SREBP) pathway as determinants of viral entry in endothelial cells and showed that membrane cholesterol has a key role in hantavirus membrane fusion14,16.
To extract hantavirus-receptor candidates from our dataset, we filtered our hits for genes that encode known plasma-membrane proteins17, and found a single gene, PCDH1-which encodes a cadherin-superfamily protein7,8, protocadherin-1-with proposed roles in...