Role of TMPRSS2 in SARS-CoV-2 induced expression of pro-inflammatory cytokines
Final Report Abstract
The cellular serine protease TMPRSS2 activates the spike protein of SARS-CoV-2 and its activity is required for efficient lung cell entry of the virus. Data published before the pandemic and obtained with TMPRSS2 knock out mice and cell cultures treated with Camostat, a serine protease inhibitor active against TMPRSS2, suggested that TMPRSS2 might promote induction of pro-inflammatory cytokines by polyIC and other stimuli. Considering that uncontrolled expression of certain pro-inflammatory cytokines is a hallmark of COVID-19, it was conceivable that TMPRSS2 might promote COVID-19 pathogenesis not only by activating the viral spike protein but also by promoting expression of pro-inflammatory cytokines. This hypothesis was to be tested, using Calu-3 lung cells, engineered to overexpress TMPRSS2 or Cathepsin L, another spike-activating protease, or in which TMPRSS2 was knocked-out via CRISPR/Cas9. RNAseq analysis of polyIC/Camostat treated Calu-3 cells provided no evidence that polyIC-mediated upregulation of pro-inflammatory cytokines or other genes modulated by SARS-CoV-2 infection was reversed by Camostat treatment. Since only Calu-3 cells stably expressing Cathepsin L could be successfully generated and shown to be functional, the effect of TMPRSS2 overexpression or knock-down on expression of proinflammatory cytokine could not be analysed. Nevertheless, the project aided several closely related efforts providing insights into SARS-CoV-2 activation and neutralization, resulting in several publications.
Publications
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B.1.617.2 enters and fuses lung cells with increased efficiency and evades antibodies induced by infection and vaccination. Cell Reports, 37(2), 109825.
Arora, Prerna; Sidarovich, Anzhalika; Krüger, Nadine; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Moldenhauer, Anna-Sophie; Winkler, Martin S.; Schulz, Sebastian; Jäck, Hans-Martin; Stankov, Metodi V.; Behrens, Georg M.N.; Pöhlmann, Stefan & Hoffmann, Markus
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Host Cell Entry and Neutralization Sensitivity of SARS-CoV-2 Lineages B.1.620 and R.1. Viruses, 14(11), 2475.
Sidarovich, Anzhalika; Krüger, Nadine; Rocha, Cheila; Graichen, Luise; Kempf, Amy; Nehlmeier, Inga; Lier, Martin; Cossmann, Anne; Stankov, Metodi V.; Schulz, Sebastian R.; Behrens, Georg M. N.; Jäck, Hans-Martin; Pöhlmann, Stefan & Hoffmann, Markus
