A suitable murine model for studying respiratory coronavirus infection and therapeutic countermeasures in BSL-2 laboratories

dos Santos Pereira Andrade, Ana Cláudia; Campolina-Silva, Gabriel Henrique; Queiroz-Junior, Celso Martins; de Oliveira, Leonardo Camilo; de Souza Barbosa Lacerda, Larisse; Pimenta, Jordane Clarisse; de Souza, Filipe Resende Oliveira; de Meira Chaves, Ian; Passos, Ingredy Beatriz; Teixeira, Danielle Cunha; Bittencourt-Silva, Paloma Graziele; Costa Valadão, Priscila Aparecida; Rossi-Oliveira, Leonardo; Antunes, Maisa Mota; Almeida Figueiredo, André Felipe; Wnuk, Natália Teixeira; Temerozo, Jairo R.; Ferreira, André Costa; Cramer, Allysson; Oliveira, Cleida Aparecida; Durães-Carvalho, Ricardo; Arns, Clarice Weis; Guimarães, Pedro Pires Goulart; Costa, Guilherme Mattos Jardim; de Menezes, Gustavo Batista; Guatimosim, Cristina; da Silva, Glauber Santos Ferreira; Souza, Thiago Moreno L.; Barrioni, Breno Rocha; de Magalhães Pereira, Marivalda; de Sousa, Lirlândia Pires; Teixeira, Mauro Martins; Costa, Vivian Vasconcelos

Several animal models are being used to explore important features of COVID-19, nevertheless none of them recapitulates all aspects of the disease in humans. The continuous refinement and development of other options of in vivo models are opportune, especially ones that are carried out at BSL-2 (Biosafety Level 2) laboratories. In this study, we investigated the suitability of the intranasal infection with the murine betacoronavirus MHV-3 to recapitulate multiple aspects of the pathogenesis of COVID-19 in C57BL/6J mice. We demonstrate that MHV-3 replicated in lungs 1 day after inoculation and triggered respiratory inflammation and dysfunction. This MHV-model of infection was further applied to highlight the critical role of TNF in cytokine-mediated coronavirus pathogenesis. Blocking TNF signaling by pharmacological and genetic strategies greatly increased the survival time and reduces lung injury of MHV-3-infected mice. In vitro studies showed that TNF blockage decreased SARS-CoV-2 replication in human epithelial lung cells and resulted in the lower release of IL-6 and IL-8 cytokines beyond TNF itself. Taken together, our results demonstrate that this model of MHV infection in mice is a useful BSL-2 screening platform for evaluating pathogenesis for human coronaviruses infections, such as COVID-19.