Prior viral respiratory infections affect the immune response against a mouse-adapted strain of sars-cov-2 and modulate disease severity in mice

Successive pulmonary infections shape the lung's immune landscape, influencing future immune responses to other pathogens. This phenomenon has been particularly evident in the context of SARS-CoV-2 infections, where some patients experienced only mild symptoms, while others required intensive care or succumbed to the virus. While many studies have examined the impact of comorbidities, few have explored the role of patients’ infection histories. In this study, we aimed to investigate how prior exposure to different respiratory viruses affects the pathogenesis of SARS-CoV-2 using preclinical models. Specifically, C57BL/6 mice were either pre-infected or not with a mouse-adapted strain of influenza (PR8), mouse adenovirus 1 (MAV1), Murid Herpesvirus 4 (MuHV4), or the pneumonia virus of mice (PVM). One month later, the mice were infected with a mouse-adapted strain of SARS-CoV-2 (MA30) [1]. Our findings revealed that mice pre-infected with MuHV4, MAV1, and PVM exhibited varying levels of protection against MA30 infection and disease, whereas those pre-infected with PR8 were sicker and had a lower survival rate. Using an Olink® cytokine quantification assay on bronchoalveolar lavage fluid (BALF) collected 4 and 8 days post-MA30 infection, we observed significant differences in the levels and kinetics of BALF cytokines. The most severely affected mice showed increased concentrations of pro-inflammatory cytokines, while those protected exhibited an early cytokine signature associated with protection. Additionally, these observations were linked to variations in leukocyte infiltrates, particularly myeloid cells, in the lungs. In conclusion, our results underscore that a history of respiratory virus infections dramatically influences the outcome of subsequent SARS-CoV-2 infections.