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Due to differences in human and murine angiotensin converting enzyme 2 (ACE-2) receptor, initially available SARS-CoV-2 isolates could not infect mice. Here we show that serial passaging of USA-WA1/2020 strain in mouse lungs results in "mouse-adapted" SARS-CoV-2 (MA-SARS-CoV-2) with mutations in S, M, and N genes, and a twelve-nucleotide insertion in the S gene. MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice. Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs). N501Y in the receptor binding domain of viruses of the B.1.1.7, B.1.351, P.1 and B.1.1.529 lineages (Alpha, Beta, Gamma and Omicron variants) is associated with high transmissibility and allows VoCs to infect wild type mice. We further show that S protein mutations of MA-SARS-CoV-2 do not affect neutralization efficiency by human convalescent and post vaccination sera., (© 2022. The Author(s).)

The risk of emerging pandemic influenza A viruses (IAVs) that approach the devastating 1918 strain motivates finding strain-specific host-pathogen mechanisms. During infection, dendritic cells (DC) mature into antigen-presenting cells that activate T cells, linking innate to adaptive immunity. DC infection with seasonal IAVs, but not with the 1918 and 2009 pandemic strains, induces global RNA degradation. Here, we show that DC infection with seasonal IAV causes immunogenic RIPK3-mediated cell death. Pandemic IAV suppresses this immunogenic DC cell death. Only DC infected with seasonal IAV, but not with pandemic IAV, enhance maturation of uninfected DC and T cell proliferation. In vivo, circulating T cell levels are reduced after pandemic, but not seasonal, IAV infection. Using recombinant viruses, we identify the HA genomic segment as the mediator of cell death inhibition. These results show how pandemic influenza viruses subvert the immune response.