PB0768 - Mouse strain specific response to a murine coronavirus respiratory infection

Background: Mouse strains are affected differently by respiratory virus infection. Using the murine betacoronavirus M-CoV, we observed distinct outcomes and severity depending on the dose and strain. Moreover, we identified a potential target that may explain strain specific differences.

Aims: Analysis of dose dependent immunomodulatory and hemostatic response in Balb/c and C57Bl/6 mice during an M-CoV infection.

Methods: Balb/c mice were infected intranasally with five different concentrations of M-CoV. Virus burden, inflammatory markers, immune response as well as histological stainings of the lung were analyzed at day 4 after the infection and compared to infected C57Bl/6. Moreover, RNA sequencing of infected Balb/c and C57Bl/6 was performed.

Results: In Balb/c animals, increasing virus concentrations resulted in corresponding increase in inflammatory markers and interferon response. Histological analysis of the lung showed dose dependent increase of neutrophil CitH4 but a decrease of thrombosis. Fibrosis occurred in all virus treated animals. T-cells decreased with rising viral concentration. In contrast, C57Bl/6 had a milder disease progression but strong, persistent thrombosis. RNA profiles revealed a dose dependent clustering of virus dosages within Balb/c. C57Bl/6 displayed a different overall RNA expression pattern. Kcnn4, a KCa3.1 channel that is expressed in the intestinal epithelium and immune cells, is progressively downregulated in high-virus Balb/c but upregulated in C57Bl/6 mice.

Conclusion(s): We observed a different respiratory infection phenotype in C57Bl/6 and Balb/c animals regarding their overall response and severity, similar to the human population. Balb/c animals were stronger affected by the infection than C57Bl/6. Immune response, inflammation and thrombosis correlated both positively and negatively with virus burden in Balb/c. Additionally, Balb/c had increased fibrosis, while C57Bl/6 had a strong thromboinflammatory phenotype. RNA sequencing revealed differences between Balb/c and C57Bl/6 animals especially in KCa3.1 which might be linked to immune cell activation and partially explain the different reactions towards the virus infection.