Since 1889 there have been six influenza A (FLUAV) pandemics, the most recent being the 2009 H1N1 pandemic (pdmH1N1). The pdmH1N1 genotype arose through reassortment events between circulating swine influenza viruses (swFLUAVs) and subsequently crossed into humans. Through multiple reverse-zoonotic events, pdmH1N1 was reintroduced into the swine population and though the full pdmH1N1 virus does not circulate in the swine population, re- introduction allowed for reassortment events resulting in new genetic constellations circulating in the swine population. Since the 1990’s, the majority of circulating swFLUAVs endemic to North America contained an internal gene segment constellation known as the triple reassortment internal gene (TRIG) cassette. Following reassortment events with pdmH1N1, the pdmH1N1 origin matrix gene (pdmM) replaced the classical swine origin matrix gene (swM) within the well-conserved TRIG cassette. Previously, we established a link correlating the origin of the matrix gene and the severity of disease induced by swFLUAV isolates in a murine model. Work by others noted greater neuraminidase activity and transmission efficiency of viruses containing the pdmM gene, supporting the hypothesis that the pdmM lends a fitness benefit to circulating swFLUAVs. The objective of this research was to determine if the origin of the matrix gene contributed to a dysregulation in the host immune response leading to increased severity of disease in a murine model. We also sought to isolate the effects of the matrix gene alone, developing a reverse genetics backbone to evaluate the changes in viral pathogenesis as well as matrix protein expression upon exchange of the matrix genes between similar swM and pdmM containing viruses. We found that the infection with swFLUAV viruses containing the pdmM gene resulted in a dysregulated immune response with greater leukocyte lung infiltrate populations and greater inflammatory cytokine and chemokine release. This dysregulated response in the lungs may contribute to the disease severity previously observed. Knowledge of these specific genetic features and how they contribute to pathogenesis, transmission, and host adaptability can aid in swFLUAV risk assessment in future potential swine origin FLUAV pandemics.