TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

Abstract

Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndromerelated coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV). In vitro, activation induces virus-cell membrane fusion at the cell surface. However, the roles of TMPRSS2 during coronavirus infection in vivo are unclear. Here, we used animal models of SARS-CoV and MERS-CoV infection to investigate the role of TMPRSS2. Th1-prone C57BL/6 mice and TMPRSS2-knockout (KO) mice were used for SARS-CoV infection, and transgenic mice expressing the human MERS-CoV receptor DPP4 (hDPP4-Tg mice) and TMPRSS2-KO hDPP4-Tg mice were used for MERS-CoV infection. After experimental infection, TMPRSS2-deficient mouse strains showed reduced body weight loss and viral kinetics in the lungs. Lack of TMPRSS2 affected the primary sites of infection and virus spread within the airway, accompanied by less severe immunopathology. However, TMPRSS2-KO mice showed weakened inflammatory chemokine and/or cytokine responses to intranasal stimulation with poly(I·C), a Toll-like receptor 3 agonist. In conclusion, TMPRSS2 plays a crucial role in viral spread within the airway of murine models infected by SARS-CoV and MERS-CoV and in the resulting immunopathology. IMPORTANCE Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal models of SARS-CoV and MERS-CoV infection. The results suggest that lack of TMPRSS2 in the airways reduces the severity of lung pathology after infection by SARS-CoV and MERS-CoV. Taken together, the results will facilitate development of novel targets for coronavirus therapy.

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

“…One can speculate that furin-mediated precleavage at the S1/S2 site in infected cells might promote subsequent TMPRSS2-dependent entry into target cells, as reported for MERS-CoV (Kleine-Weber et al, 2018;Park et al, 2016). Collectively, our present findings and previous work highlight TMPRSS2 as a host cell factor that is critical for spread of several clinically relevant viruses, including influenza A viruses and coronaviruses (Gierer et al, 2013;Glowacka et al, 2011;Iwata-Yoshikawa et al, 2019;Kawase et al, 2012;Matsuyama et al, 2010;Shulla et al, 2011;Zhou et al, 2015). In contrast, TMPRSS2 is dispensable for development and homeostasis (Kim et al, 2006) and thus constitutes an attractive drug target.…”

“…SARS-CoV can use the endosomal cysteine proteases cathepsin B and L (CatB/L) (Simmons et al, 2005) and the serine protease TMPRSS2 (Glowacka et al, 2011;Matsuyama et al, 2010;Shulla et al, 2011) for S protein priming in cell lines, and inhibition of both proteases is required for robust blockade of viral entry (Kawase et al, 2012). However, only TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host whereas CatB/L activity is dispensable (Iwata-Yoshikawa et al, 2019;Shirato et al, 2016;Shirato et al, 2018;Zhou et al, 2015).…”

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

“…Hoffman et al [25] recently demonstrated that initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is essential for entry and viral spread of SARS-CoV-2 through interaction with the ACE2 receptor [26,27]. The serine protease inhibitor camostat mesylate, approved in Japan to treat unrelated diseases, has been shown to block TMPRSS2 activity [28,29] and is thus an interesting candidate.…”

Recent progress in understanding 2019 novel coronavirus (SARS-CoV-2) associated with human respiratory disease: detection, mechanisms and treatment

“…A non-critical SARS-CoV-2infected patient in South Korea received lopinavir/ritonavir (Kaletra; AbbVie) on the eighth day of admission, after which the clinical symptoms improved and the coronavirus load began to decrease until undetectable [77] . Animal models suggest that TM-PRSS2 (type II transmembrane serine protease) plays an important role in coronavirus transmission [78] . TMPRSS2 activates the S protein of highly pathogenic human coronavirus, which binds to the receptor ACE2 and enters host cells [30 , 42 , 78-80] .…”