A Biosafety Level 2 Mouse Model for Studying Betacoronavirus- Induced Acute Lung Damage and Systemic Manifestations

Author(s):Show less -

dos Santos Pereira Andrade, Ana Claudia ^[1] ; Campolina-Silva, Gabriel Henrique ^[2] ; Queiroz-Junior, Celso Martins ^[1] ; de Oliveira, Leonardo Camilo ^[1] ; Lacerda, Larisse de Souza Barbosa ^[1] ; Pimenta Gaggino, Jordane Clarisse ^[1] ; Oliveira de Souza, Filipe Resende ^[1] ; Chaves, Ian de Meira ^[1] ; Passos, Ingredy Beatriz ^[3] ; Teixeira, Danielle Cunha ^[1] ; Bittencourt-Silva, Paloma Graziele ^[4] ; Costa Valadao, Priscila Aparecida ^[1] ; Rossi-Oliveira, Leonardo ^[1] ; Antunes, Maisa Mota ^[1] ; Almeida Figueiredo, Andre Felipe ^[1] ; Wnuk, Natalia Teixeira ^[1] ; Temerozo, Jairo R. ^{[5, 6]} ; Ferreira, Andre Costa ^{[7, 8, 9]} ; Cramer, Allysson ^[2] ; Oliveira, Cleida Aparecida ^[1] ; Duraes-Carvalho, Ricardo ^[10] ; Arns, Clarice Weis ^[10] ; Goulart Guimaraes, Pedro Pires ^[4] ; Jardim Costa, Guilherme Mattos ^[1] ; de Menezes, Gustavo Batista ^[1] ; Guatimosim, Cristina ^[1] ; Ferreira da Silva, Glauber Santos ^[4] ; Souza, Thiago Moreno L. ^{[7, 8]} ; Barrioni, Breno Rocha ^[11] ; Pereira, Marivalda de Magalhaes ^[11] ; de Sousa, Lirlandia Pires ^[12] ; Teixeira, Mauro Martins ^[2] ; Costa, Vivian Vasconcelos ^{[2, 1]}

Affiliation:Show less -

^[1] Univ Fed Minas Gerais, Inst Biol Sci, Dept Morphol, Belo Horizonte, MG - Brazil

^[2] Univ Fed Minas Gerais, Inst Biol Sci, Dept Biochem & Immunol, Belo Horizonte, MG - Brazil

^[3] Univ Fed Minas Gerais, Inst Biol Sci, Dept Microbiol, Belo Horizonte, MG - Brazil

^[4] Univ Fed Minas Gerais, Inst Biol Sci, Dept Physiol & Biophys, Belo Horizonte, MG - Brazil

^[5] Fiocruz MS, Lab Thymus Res, Oswaldo Cruz Inst, Rio De Janeiro, RJ - Brazil

^[6] Oswaldo Cruz Fdn Fiocruz, Natl Inst Sci & Technol Neuroimmunomodulat, Rio De Janeiro, RJ - Brazil

^[7] Oswaldo Cruz Fdn Fiocruz, Ctr Technol Dev Hlth CDTS, Natl Inst Sci & Technol Innovat Dis Neglected Pop, Rio De Janeiro, RJ - Brazil

^[8] Oswaldo Cruz Fdn Fiocruz, Immunopharmacol Lab, Rio De Janeiro, RJ - Brazil

^[9] Univ Iguacu UNIG, Lab Pesquisas Preclin, Rio De Janeiro, RJ - Brazil

^[10] Univ Estadual Campinas UNICAMP, Lab Virol, Campinas, SP - Brazil

^[11] Univ Fed Minas Gerais, Sch Engn, Dept Met Engn & Mat, Belo Horizonte, MG - Brazil

^[12] Univ Fed Minas Gerais, Fac Pharm, Dept Clin & Toxicol Anal, Belo Horizonte, MG - Brazil

• Document type: Journal article
• Source: Journal of Virology; v. 95, n. 22 NOV 2021.
• Web of Science Citations: 0

Abstract

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-1 beta), IL-6, IL-12, gamma interferon (IFN-gamma), 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. (AU)

• FAPESP's process: 19/01255-9 - Bats: epidemiological surveillance, high-resolution phylodynamics, search and design of peptides of biotechnological interest in emergent and reemerging viruses
• Grantee: Ricardo Durães de Carvalho
• Support Opportunities: Research Grants - Young Investigators Grants