Protocadherin-1 is essential for cell entry by New World hantaviruses

Rohit K. Jangra; Andrew S. Herbert; Rong Li; Lucas T. Jae; Lara M. Kleinfelter; Megan M. Slough; Sarah L. Barker; Pablo Guardado-Calvo; Gleyder Román-Sosa; M. Eugenia Dieterle; Ana I. Kuehne; Nicolás A. Muena; Ariel S. Wirchnianski; Elisabeth K. Nyakatura; J. Maximilian Fels; Melinda Ng; Eva Mittler; James Pan; Sushma Bharrhan; Anna Z. Wec; Jonathan R. Lai; Sachdev S. Sidhu; Nicole D. Tischler; Félix A. Rey; Jason Moffat; Thijn R. Brummelkamp; Zhongde Wang; John M. Dye; Kartik Chandran

doi:10.1038/s41586-018-0702-1

Protocadherin-1 is essential for cell entry by New World hantaviruses

Rohit K. Jangra, Andrew S. Herbert, Rong Li, Lucas T. Jae, Lara M. Kleinfelter, Megan M. Slough, Sarah L. Barker, Pablo Guardado-Calvo, Gleyder Román-Sosa, M. Eugenia Dieterle, Ana I. Kuehne, Nicolás A. Muena, Ariel S. Wirchnianski, Elisabeth K. Nyakatura, J. Maximilian Fels, Melinda Ng, Eva Mittler, James Pan, Sushma Bharrhan, Anna Z. WecJonathan R. Lai, Sachdev S. Sidhu, Nicole D. Tischler, Félix A. Rey, Jason Moffat, Thijn R. Brummelkamp, Zhongde Wang, John M. Dye, Kartik Chandran

Research output: Contribution to journal › Article › peer-review

67 Scopus citations

Abstract

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 superfamily^7,8—to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

Original language	English (US)
Pages (from-to)	559-563
Number of pages	5
Journal	Nature
Volume	563
Issue number	7732
DOIs	https://doi.org/10.1038/s41586-018-0702-1
State	Published - Nov 22 2018

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10.1038/s41586-018-0702-1

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Jangra, R. K., Herbert, A. S., Li, R., Jae, L. T., Kleinfelter, L. M., Slough, M. M., Barker, S. L., Guardado-Calvo, P., Román-Sosa, G., Dieterle, M. E., Kuehne, A. I., Muena, N. A., Wirchnianski, A. S., Nyakatura, E. K., Fels, J. M., Ng, M., Mittler, E., Pan, J., Bharrhan, S., ... Chandran, K. (2018). Protocadherin-1 is essential for cell entry by New World hantaviruses. Nature, 563(7732), 559-563. https://doi.org/10.1038/s41586-018-0702-1

Jangra, RK, Herbert, AS, Li, R, Jae, LT, Kleinfelter, LM, Slough, MM, Barker, SL, Guardado-Calvo, P, Román-Sosa, G, Dieterle, ME, Kuehne, AI, Muena, NA, Wirchnianski, AS, Nyakatura, EK, Fels, JM, Ng, M, Mittler, E, Pan, J, Bharrhan, S, Wec, AZ, Lai, JR, Sidhu, SS, Tischler, ND, Rey, FA, Moffat, J, Brummelkamp, TR, Wang, Z, Dye, JM & Chandran, K 2018, 'Protocadherin-1 is essential for cell entry by New World hantaviruses', Nature, vol. 563, no. 7732, pp. 559-563. https://doi.org/10.1038/s41586-018-0702-1

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title = "Protocadherin-1 is essential for cell entry by New World hantaviruses",

abstract = "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 PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.",

author = "Jangra, {Rohit K.} and Herbert, {Andrew S.} and Rong Li and Jae, {Lucas T.} and Kleinfelter, {Lara M.} and Slough, {Megan M.} and Barker, {Sarah L.} and Pablo Guardado-Calvo and Gleyder Rom{\'a}n-Sosa and Dieterle, {M. Eugenia} and Kuehne, {Ana I.} and Muena, {Nicol{\'a}s A.} and Wirchnianski, {Ariel S.} and Nyakatura, {Elisabeth K.} and Fels, {J. Maximilian} and Melinda Ng and Eva Mittler and James Pan and Sushma Bharrhan and Wec, {Anna Z.} and Lai, {Jonathan R.} and Sidhu, {Sachdev S.} and Tischler, {Nicole D.} and Rey, {F{\'e}lix A.} and Jason Moffat and Brummelkamp, {Thijn R.} and Zhongde Wang and Dye, {John M.} and Kartik Chandran",

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doi = "10.1038/s41586-018-0702-1",

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AU - Jangra, Rohit K.

AU - Herbert, Andrew S.

AU - Li, Rong

AU - Jae, Lucas T.

AU - Kleinfelter, Lara M.

AU - Slough, Megan M.

AU - Barker, Sarah L.

AU - Guardado-Calvo, Pablo

AU - Román-Sosa, Gleyder

AU - Dieterle, M. Eugenia

AU - Kuehne, Ana I.

AU - Muena, Nicolás A.

AU - Wirchnianski, Ariel S.

AU - Nyakatura, Elisabeth K.

AU - Fels, J. Maximilian

AU - Ng, Melinda

AU - Mittler, Eva

AU - Pan, James

AU - Bharrhan, Sushma

AU - Wec, Anna Z.

AU - Lai, Jonathan R.

AU - Sidhu, Sachdev S.

AU - Tischler, Nicole D.

AU - Rey, Félix A.

AU - Moffat, Jason

AU - Brummelkamp, Thijn R.

AU - Wang, Zhongde

AU - Dye, John M.

AU - Chandran, Kartik

PY - 2018/11/22

Y1 - 2018/11/22

N2 - 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 PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

AB - 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 PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

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VL - 563

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EP - 563

JO - Nature

JF - Nature

IS - 7732

ER -

Protocadherin-1 is essential for cell entry by New World hantaviruses

Abstract

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