Tags

Type your tag names separated by a space and hit enter

Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response.
J Virol. 2011 May; 85(9):4122-34.JV

Abstract

The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targets treated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARS-CoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion.

Authors+Show Affiliations

Institute of Virology, Hannover Medical School, 30625 Hannover, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21325420

Citation

Glowacka, Ilona, et al. "Evidence That TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control By the Humoral Immune Response." Journal of Virology, vol. 85, no. 9, 2011, pp. 4122-34.
Glowacka I, Bertram S, Müller MA, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85(9):4122-34.
Glowacka, I., Bertram, S., Müller, M. A., Allen, P., Soilleux, E., Pfefferle, S., Steffen, I., Tsegaye, T. S., He, Y., Gnirss, K., Niemeyer, D., Schneider, H., Drosten, C., & Pöhlmann, S. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Journal of Virology, 85(9), 4122-34. https://doi.org/10.1128/JVI.02232-10
Glowacka I, et al. Evidence That TMPRSS2 Activates the Severe Acute Respiratory Syndrome Coronavirus Spike Protein for Membrane Fusion and Reduces Viral Control By the Humoral Immune Response. J Virol. 2011;85(9):4122-34. PubMed PMID: 21325420.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. AU - Glowacka,Ilona, AU - Bertram,Stephanie, AU - Müller,Marcel A, AU - Allen,Paul, AU - Soilleux,Elizabeth, AU - Pfefferle,Susanne, AU - Steffen,Imke, AU - Tsegaye,Theodros Solomon, AU - He,Yuxian, AU - Gnirss,Kerstin, AU - Niemeyer,Daniela, AU - Schneider,Heike, AU - Drosten,Christian, AU - Pöhlmann,Stefan, Y1 - 2011/02/16/ PY - 2011/2/18/entrez PY - 2011/2/18/pubmed PY - 2011/6/15/medline SP - 4122 EP - 34 JF - Journal of virology JO - J. Virol. VL - 85 IS - 9 N2 - The spike (S) protein of the severe acute respiratory syndrome coronavirus (SARS-CoV) can be proteolytically activated by cathepsins B and L upon viral uptake into target cell endosomes. In contrast, it is largely unknown whether host cell proteases located in the secretory pathway of infected cells and/or on the surface of target cells can cleave SARS S. We along with others could previously show that the type II transmembrane protease TMPRSS2 activates the influenza virus hemagglutinin and the human metapneumovirus F protein by cleavage. Here, we assessed whether SARS S is proteolytically processed by TMPRSS2. Western blot analysis revealed that SARS S was cleaved into several fragments upon coexpression of TMPRSS2 (cis-cleavage) and upon contact between SARS S-expressing cells and TMPRSS2-positive cells (trans-cleavage). cis-cleavage resulted in release of SARS S fragments into the cellular supernatant and in inhibition of antibody-mediated neutralization, most likely because SARS S fragments function as antibody decoys. trans-cleavage activated SARS S on effector cells for fusion with target cells and allowed efficient SARS S-driven viral entry into targets treated with a lysosomotropic agent or a cathepsin inhibitor. Finally, ACE2, the cellular receptor for SARS-CoV, and TMPRSS2 were found to be coexpressed by type II pneumocytes, which represent important viral target cells, suggesting that SARS S is cleaved by TMPRSS2 in the lung of SARS-CoV-infected individuals. In summary, we show that TMPRSS2 might promote viral spread and pathogenesis by diminishing viral recognition by neutralizing antibodies and by activating SARS S for cell-cell and virus-cell fusion. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/21325420/Evidence_that_TMPRSS2_activates_the_severe_acute_respiratory_syndrome_coronavirus_spike_protein_for_membrane_fusion_and_reduces_viral_control_by_the_humoral_immune_response_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=21325420 DB - PRIME DP - Unbound Medicine ER -