Prior influenza infection mitigates SARS-CoV-2 disease in Syrian hamsters

Seasonal infection rates of individual viruses are influenced by synergistic or inhibitory interactions between coincident viruses. Endemic patterns of SARS-CoV-2 and influenza infection overlap seasonally in the Northern hemisphere and may be similarly influenced. We explored the immunopathologic basis of SARS-CoV-2 and influenza A (H1N1) interactions in Syrian hamsters. H1N1 given 48 hours prior to SARS-CoV-2 profoundly mitigated weight loss and lung pathology compared to SARS-CoV-2 infection alone. This was accompanied by normalization of granulocyte dynamics and accelerated antigen presenting populations in bronchoalveolar lavage and blood. Using nasal transcriptomics, we identified rapid upregulation of innate and antiviral pathways induced by H1N1 by the time of SARS-CoV-2 inoculation in 48 hour dual infected animals. Dual infected animals also experienced significant transient downregulation of mitochondrial and viral replication pathways. By quantitative RT-PCR, we confirmed reduced SARS-CoV-2 viral load and lower cytokine levels throughout disease course in lung of dual infected animals. Our data confirm that H1N1 infection induces rapid and transient gene expression that is associated with mitigation of SARS-CoV-2 pulmonary disease. These protective responses are likely to begin in the upper respiratory tract shortly after infection. On a population level, interaction between these two viruses may influence their relative seasonal infection rates. Overall design: We infected 6-8 week old Syrian hamsters intranasally with Influenza (Influenza virus A/Michigan/45/2015 (H1N1) pdm09), followed by infection with SARS-CoV-2 (SARS-CoV-2 Wuhan/IVDC-HB-01/2019) given intranasally 48 hours later. Four infection groups were used: H1N1 infection only (n=6), SARS-CoV-2 infection only (n=6), H1N1 infection followed by SARS-CoV-2 infection 48 hours later (n=6), and mock infected (n=4). All animals were males. Animals were sacrificed at Day 1 (n=3 per infection type) and Day 2 (n=3 per infection type) after their last infection. Nasal epithelium was collected under sterile conditions for RNA sequencing. . We compared differential gene expression in infected vs mock control animals, as well as differential gene expression between infection types at comparable days post infection.