Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis

• Published in: Experimental & molecular medicine Vol. 56; no. 5; pp. 1221 - 1229
• Main Authors: Jeong, Gi Uk, Hwang, Insu, Lee, Wooseong, Choi, Ji Hyun, Yoon, Gun Young, Kim, Hae Soo, Yang, Jeong-Sun, Kim, Kyung-Chang, Lee, Joo-Yeon, Kim, Seong-Jun, Kwon, Young-Chan, Kim, Kyun-Do
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/21; 13/51; 14/1; 42/109; 42/44; 631/1647/334/2045; 631/250/255/2514; 64/110; ACE2; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animal models; Animals; Antiviral agents; Artificial intelligence; Benzamidines; Biomedical and Life Sciences; Biomedicine; Body weight loss; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - metabolism; COVID-19 - virology; COVID-19 Drug Treatment; Disease Models, Animal; Enzymes; Guanidines - pharmacology; Humans; Infections; Infectivity; Lethality; Lung diseases; Medical Biochemistry; Mice; Mice, Transgenic; Molecular Medicine; Pathogenesis; Peptidyl-dipeptidase A; Replication; SARS-CoV-2 - genetics; SARS-CoV-2 - physiology; Serine Endopeptidases - genetics; Serine Endopeptidases - metabolism; Serine proteinase; Severe acute respiratory syndrome coronavirus 2; Stem Cells; Transgenic animals; Transgenic mice; Viral infections; Virus Replication; Viruses
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01197-z

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019. Unveiling susceptibility of SARS-CoV-2 variants in double-transgenic mice This research aimed to create a type of mouse that is very prone to SARS-CoV-2 infection, the virus that causes COVID-19. Scientists from two Korean research institutes found that mice with both human angiotensin-converting enzyme 2 (hACE2, a protein that the virus uses to enter cells) and human transmembrane serine protease 2 (hTMPRSS2, an enzyme that helps the virus to infect cells) were very prone to the virus. They created mice with both these human genes, infected them with different amounts of SARS-CoV-2, and observed significant weight loss, disease symptoms, and death, similar to what happens in COVID-19 patients. The scientists concluded that these mice could help us understand how the virus infects and causes disease, and test potential treatments against COVID-19. The study could also help in developing future drugs and vaccines. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.