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Abstract
The 2009 H1N1 influenza pandemic caused millions of infections and thousands of deaths in the United States alone. The spread of this virus worldwide, as well as the propensity for it to cause disease in children and young adults previously considered healthy, was a major cause for concern. The pandemic H1N1 influenza strain was the result of a quadruple reassortment event with other circulating influenza strains and entered back into the swine population via multiple reverse zoonotic events. Although this strain never became endemic in North American swine, some of its gene segments, including the matrix gene, has become predominant completely replacing the classical swine matrix gene in current circulating strains in North America. Previous studies have linked a more filamentous morphology, greater neuraminidase activity, and higher transmission efficiency with the pandemic origin matrix gene. The objective of this research was to evaluate the pandemic origin matrix gene to increase disease severity. A second objective of this research was to elucidate additional host factors that could contribute to increased disease susceptibility. Herein, we demonstrate that infection with swine influenza strains containing the pandemic origin matrix gene induces more severe histopathologic changes in the lungs resulting in greater morbidity and mortality relative to infection with swine influenza strains containing the swine origin matrix gene in the murine model. Furthermore, the increase in severity of disease can in part be attributed to the dysregulation of the host innate immune response in the form of disproportionate recruitment of specific host innate immune cells as well as greater activation of neutrophils and NK cells during infection with swine influenza strains containing the pandemic origin matrix gene. To focus on additional host factors that contribute to influenza susceptibility, we compared the host innate immune response to influenza infection in phenotypically resistant (BALB/c) and susceptible (DBA/2) murine strains in an infection model that retained the previously established difference in morbidity, while minimizing the characteristic differences in replication. We demonstrate that the characteristic hyperinflammatory response in DBA/2 mice is attributed in part due to the dysregulation of the innate immune response distinguished by limited production of anti-inflammatory cytokines and a limited antiviral response despite high interferon production. Taken together, the research presented here demonstrates the importance of understanding the effects both viral and host factors can have on the development of disease, in order to mitigate the potential disease burden of seasonal or pandemic influenza.