TMPRSS2 plays a role in replication and pathogenesis of SARS-CoV and MERS-CoV in mice
Naoko Iwata-Yoshikawa1, Tadashi Okamura2, Makoto Takeda3, Hideki Hasegawa1,
and Noriyo Nagata1
1. Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
2. Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
3. Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan.
The type II transmembrane protease TMPRSS2, expressed by cells in the human airways and alveolae, facilitates entry of some human coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in cultured cells. Here, we used animal models of SARS and MERS-CoV to examine the role of TMPRSS2 in coronavirus infection in vivo. TMPRSS2 knockout (KO) and wild type (WT) mice were inoculated with intranasally with mouse-adapted SARS-CoV. In addition, TMPRSS2 kockout mice expressing human dipeptidyl peptidase 4 (a receptor for MERS-CoV) (KO-Tg) and hDPP4 Tg mice (Tg) were inoculated intranasally with MERS-CoV.
KO mice infected with SARS-CoV showed no weight loss during the 10 day observation period; however, WT mice lost 10-15% of their bodyweight. Viral titers in the lungs of KO mice were lower than in those of WT mice during 3 days p.i. At 1 dpi, KO mice harbored fewer virus antigen-positive cells in the lung than WT mice. Inflammatory cytokine levels including IL-12 in the lungs from KO mice were lower than that from WT mice. MERS-CoV infection of KO-Tg mice yielded results similar to the SARS-CoV study. KO-Tg mice showed very slight weight loss after infection, and the viral titer detected in the lung at 1 dpi was 10-fold lower than that in Tg mice. Also, the lungs of KO-Tg mice harbored fewer virus antigen-positive cells at 1 dpi than those of Tg mice. Additionally, lung pathology in KO-Tg mice was milder than that in hDPP4 mice throughout 7 dpi.
In conclusion, lack of TMPRSS2 expression in vivo reduced the severity of clinical symptoms, restricted SARS-CoV and MERS-CoV replication, and reduced lung pathology. Thus, TMPRSS2 promotes replication and lung pathogenesis mediated by coronavirus.