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Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection.
J Virol. 2020 02 14; 94(5)JV

Abstract

Traditionally, the emergence of coronaviruses (CoVs) has been attributed to a gain in receptor binding in a new host. Our previous work with severe acute respiratory syndrome (SARS)-like viruses argued that bats already harbor CoVs with the ability to infect humans without adaptation. These results suggested that additional barriers limit the emergence of zoonotic CoV. In this work, we describe overcoming host restriction of two Middle East respiratory syndrome (MERS)-like bat CoVs using exogenous protease treatment. We found that the spike protein of PDF2180-CoV, a MERS-like virus found in a Ugandan bat, could mediate infection of Vero and human cells in the presence of exogenous trypsin. We subsequently show that the bat virus spike can mediate the infection of human gut cells but is unable to infect human lung cells. Using receptor-blocking antibodies, we show that infection with the PDF2180 spike does not require MERS-CoV receptor DPP4 and antibodies developed against the MERS spike receptor-binding domain and S2 portion are ineffective in neutralizing the PDF2180 chimera. Finally, we found that the addition of exogenous trypsin also rescues HKU5-CoV, a second bat group 2c CoV. Together, these results indicate that proteolytic cleavage of the spike, not receptor binding, is the primary infection barrier for these two group 2c CoVs. Coupled with receptor binding, proteolytic activation offers a new parameter to evaluate the emergence potential of bat CoVs and offers a means to recover previously unrecoverable zoonotic CoV strains.IMPORTANCE Overall, our studies demonstrate that proteolytic cleavage is the primary barrier to infection for a subset of zoonotic coronaviruses. Moving forward, the results argue that both receptor binding and proteolytic cleavage of the spike are critical factors that must be considered for evaluating the emergence potential and risk posed by zoonotic coronaviruses. In addition, the findings also offer a novel means to recover previously uncultivable zoonotic coronavirus strains and argue that other tissues, including the digestive tract, could be a site for future coronavirus emergence events in humans.

Authors+Show Affiliations

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.Department of Cell Biology and Physiology, and Marsico Lung Institute/Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Rbaric@email.unc.edu. Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

31801868

Citation

Menachery, Vineet D., et al. "Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection." Journal of Virology, vol. 94, no. 5, 2020.
Menachery VD, Dinnon KH, Yount BL, et al. Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection. J Virol. 2020;94(5).
Menachery, V. D., Dinnon, K. H., Yount, B. L., McAnarney, E. T., Gralinski, L. E., Hale, A., Graham, R. L., Scobey, T., Anthony, S. J., Wang, L., Graham, B., Randell, S. H., Lipkin, W. I., & Baric, R. S. (2020). Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection. Journal of Virology, 94(5). https://doi.org/10.1128/JVI.01774-19
Menachery VD, et al. Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection. J Virol. 2020 02 14;94(5) PubMed PMID: 31801868.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection. AU - Menachery,Vineet D, AU - Dinnon,Kenneth H,3rd AU - Yount,Boyd L,Jr AU - McAnarney,Eileen T, AU - Gralinski,Lisa E, AU - Hale,Andrew, AU - Graham,Rachel L, AU - Scobey,Trevor, AU - Anthony,Simon J, AU - Wang,Lingshu, AU - Graham,Barney, AU - Randell,Scott H, AU - Lipkin,W Ian, AU - Baric,Ralph S, Y1 - 2020/02/14/ PY - 2019/10/16/received PY - 2019/11/27/accepted PY - 2019/12/6/pubmed PY - 2020/6/24/medline PY - 2019/12/6/entrez KW - MERS-CoV KW - PDF2180 KW - coronavirus KW - emergence KW - spike KW - zoonotic JF - Journal of virology JO - J Virol VL - 94 IS - 5 N2 - Traditionally, the emergence of coronaviruses (CoVs) has been attributed to a gain in receptor binding in a new host. Our previous work with severe acute respiratory syndrome (SARS)-like viruses argued that bats already harbor CoVs with the ability to infect humans without adaptation. These results suggested that additional barriers limit the emergence of zoonotic CoV. In this work, we describe overcoming host restriction of two Middle East respiratory syndrome (MERS)-like bat CoVs using exogenous protease treatment. We found that the spike protein of PDF2180-CoV, a MERS-like virus found in a Ugandan bat, could mediate infection of Vero and human cells in the presence of exogenous trypsin. We subsequently show that the bat virus spike can mediate the infection of human gut cells but is unable to infect human lung cells. Using receptor-blocking antibodies, we show that infection with the PDF2180 spike does not require MERS-CoV receptor DPP4 and antibodies developed against the MERS spike receptor-binding domain and S2 portion are ineffective in neutralizing the PDF2180 chimera. Finally, we found that the addition of exogenous trypsin also rescues HKU5-CoV, a second bat group 2c CoV. Together, these results indicate that proteolytic cleavage of the spike, not receptor binding, is the primary infection barrier for these two group 2c CoVs. Coupled with receptor binding, proteolytic activation offers a new parameter to evaluate the emergence potential of bat CoVs and offers a means to recover previously unrecoverable zoonotic CoV strains.IMPORTANCE Overall, our studies demonstrate that proteolytic cleavage is the primary barrier to infection for a subset of zoonotic coronaviruses. Moving forward, the results argue that both receptor binding and proteolytic cleavage of the spike are critical factors that must be considered for evaluating the emergence potential and risk posed by zoonotic coronaviruses. In addition, the findings also offer a novel means to recover previously uncultivable zoonotic coronavirus strains and argue that other tissues, including the digestive tract, could be a site for future coronavirus emergence events in humans. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/31801868/Trypsin_Treatment_Unlocks_Barrier_for_Zoonotic_Bat_Coronavirus_Infection_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31801868/ DB - PRIME DP - Unbound Medicine ER -