A Biosafety Level 2 Mouse Model for Studying Betacoronavirus-Induced Acute Lung Damage and Systemic Manifestations.
The emergence of life-threatening zoonotic diseases caused by betacoronaviruses, including the ongoing coronavirus disease 19 (COVID-19) pandemic, has highlighted the need for developing preclinical models mirroring respiratory and systemic pathophysiological manifestations seen in infected humans. Here, we showed that C57BL/6J wild-type mice intranasally inoculated with the murine betacoronavirus murine hepatitis coronavirus 3 (MHV-3) develop a robust inflammatory response leading to acute lung injuries, including alveolar edema, hemorrhage, and fibrin thrombi. Although such histopathological changes seemed to resolve as the infection advanced, they efficiently impaired respiratory function, as the infected mice displayed restricted lung distention and increased respiratory frequency and ventilation. Following respiratory manifestation, the MHV-3 infection became systemic, and a high virus burden could be detected in multiple organs along with morphological changes. The systemic manifestation of MHV-3 infection was also marked by a sharp drop in the number of circulating platelets and lymphocytes, besides the augmented concentration of the proinflammatory cytokines interleukin 1 beta (IL-1β), IL-6, IL-12, gamma interferon (IFN-γ), and tumor necrosis factor (TNF), thereby mirroring some clinical features observed in moderate and severe cases of COVID-19. Importantly, both respiratory and systemic changes triggered by MHV-3 infection were greatly prevented by blocking TNF signaling, either via genetic or pharmacologic approaches. In line with this, TNF blockage also diminished the infection-mediated release of proinflammatory cytokines and virus replication of human epithelial lung cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Collectively, results show that MHV-3 respiratory infection leads to a large range of clinical manifestations in mice and may constitute an attractive, lower-cost, biosafety level 2 (BSL2) in vivo platform for evaluating the respiratory and multiorgan involvement of betacoronavirus infections. IMPORTANCE Mouse models have long been used as valuable in vivo platforms to investigate the pathogenesis of viral infections and effective countermeasures. The natural resistance of mice to the novel betacoronavirus SARS-CoV-2, the causative agent of COVID-19, has launched a race toward the characterization of SARS-CoV-2 infection in other animals (e.g., hamsters, cats, ferrets, bats, and monkeys), as well as adaptation of the mouse model, by modifying either the host or the virus. In the present study, we utilized a natural pathogen of mice, MHV, as a prototype to model betacoronavirus-induced acute lung injure and multiorgan involvement under biosafety level 2 conditions. We showed that C57BL/6J mice intranasally inoculated with MHV-3 develops severe disease, which includes acute lung damage and respiratory distress that precede systemic inflammation and death. Accordingly, the proposed animal model may provide a useful tool for studies regarding betacoronavirus respiratory infection and related diseases.
['Andrade|Ana Cláudia Dos Santos Pereira|ACDSP|', 'Campolina-Silva|Gabriel Henrique|GH|', 'Queiroz-Junior|Celso Martins|CM|', 'de Oliveira|Leonardo Camilo|LC|', 'Lacerda|Larisse de Souza Barbosa|LSB|', 'Gaggino|Jordane Clarisse Pimenta|JCP|', 'de Souza|Filipe Resende Oliveira|FRO|', 'de Meira Chaves|Ian|I|', 'Passos|Ingredy Beatriz|IB|', 'Teixeira|Danielle Cunha|DC|', 'Bittencourt-Silva|Paloma Graziele|PG|', 'Valadão|Priscila Aparecida Costa|PAC|', 'Rossi-Oliveira|Leonardo|L|', 'Antunes|Maisa Mota|MM|', 'Figueiredo|André Felipe Almeida|AFA|', 'Wnuk|Natália Teixeira|NT|', 'Temerozo|Jairo R|JR|0000-0002-8092-2149', 'Ferreira|André Costa|AC|', 'Cramer|Allysson|A|', 'Oliveira|Cleida Aparecida|CA|', 'Durães-Carvalho|Ricardo|R|0000-0001-5734-7601', 'Weis Arns|Clarice|C|', 'Guimarães|Pedro Pires Goulart|PPG|', 'Costa|Guilherme Mattos Jardim|GMJ|', 'de Menezes|Gustavo Batista|GB|', 'Guatimosim|Cristina|C|', 'da Silva|Glauber Santos Ferreira|GSF|', 'Souza|Thiago Moreno L|TML|', 'Barrioni|Breno Rocha|BR|', 'Pereira|Marivalda de Magalhães|MM|', 'de Sousa|Lirlândia Pires|LP|', 'Teixeira|Mauro Martins|MM|', 'Costa|Vivian Vasconcelos|VV|0000-0002-0175-642X']
D000818:Animals D002460:Cell Line D003264:Containment of Biohazards D018352:Coronavirus Infections D016207:Cytokines D004195:Disease Models, Animal D006801:Humans D007249:Inflammation D008099:Liver D008168:Lung D051379:Mice D006517:Murine hepatitis virus D000086402:SARS-CoV-2 D015398:Signal Transduction D014409:Tumor Necrosis Factor-alpha D014779:Virus Replication
COVID-19 betacoronavirus MHV-3 tumor necrosis factor animal model lung infection