+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Journal of Virology 93(6):



Transmembrane serine protease TMPRSS2 activates the spike protein of highly pathogenic human coronaviruses such as severe acute respiratory syndrome-related 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.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 066075175

Download citation: RISBibTeXText

PMID: 30626688


Related references

Murine coronavirus spike glycoprotein mediates degree of viral spread, inflammation, and virus-induced immunopathology in the central nervous system. Virology 301(1): 9-20, 2002

Failure to spread bovine virus diarrhoea virus infection from primarily infected calves despite concurrent infection with bovine coronavirus. Veterinary journal 163(3): 251-259, 2002

Severe acute respiratory syndrome coronavirus infection of human ciliated airway epithelia: role of ciliated cells in viral spread in the conducting airways of the lungs. Journal of Virology 79(24): 15511-15524, 2005

The spike glycoprotein of murine coronavirus MHV-JHM mediates receptor-independent infection and spread in the central nervous systems of Ceacam1a-/- Mice. Journal of Virology 82(2): 755-763, 2008

TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. Journal of Virology 88(2): 1293-1307, 2014

Coronavirus infection in mink (Mustela vison). Serological evidence of infection with a coronavirus related to transmissible gastroenteritis virus and porcine epidemic diarrhea virus. Veterinary Microbiology 31(1): 1-10, 1992

TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 142: 1-10, 2017

Deficient incorporation of spike protein into virions contributes to the lack of infectivity following establishment of a persistent, non-productive infection in oligodendroglial cell culture by murine coronavirus. Virology 409(1): 121-131, 2011

Murine coronavirus receptors are differentially expressed in the central nervous system and play virus strain-dependent roles in neuronal spread. Journal of Virology 84(21): 11030-11044, 2010

Antiviral effects of antisense morpholino oligomers in murine coronavirus infection models. Journal of Virology 81(11): 5637-5648, 2007

Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. Journal of Virology 87(23): 12552-12561, 2013

Immunopathology of Chikungunya Virus Infection: Lessons Learned from Patients and Animal Models. Annual Review of Virology 4(1): 413-427, 2017

Murine coronavirus infection: a paradigm for virus-induced demyelinating disease. Trends in Microbiology 5(1): 9, 1997

The role of gE in the spread of HSV in two models of murine corneal infection. Molecular Biology of the Cell 9(Suppl. ): 354A, 1998

Murine Leukemia Virus (MLV)-based Coronavirus Spike-pseudotyped Particle Production and Infection. Bio-Protocol6(23):, 2016