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Item Initiation and pathogenesis of Staphylococcus aureus Pneumonia following influenza A infection(Montana State University - Bozeman, College of Letters & Science, 2019) Borgogna, Timothy Ryan; Chairperson, Graduate Committee: Jovanka Voyich-Kane; Adrian Sanchez-Gonzalez, Kelly Gorham and Jovanka M. Voyich were co-authors of the article, 'A precise pathogen delivery and recovery system for murine models of secondary bacterial pneumonia' in the journal 'JOVE Journal of visualized experiments' which is contained within this dissertation.; Bennett Hisey, Emily Heitman, Joshua J. Obar, Nicole Meissner and Jovanka M. Voyich were co-authors of the article, 'Secondary bacterial pneumonia by Staphylococcus aureus following influenza A infection is saeR/S dependent' in the journal 'Journal of infectious diseases' which is contained within this dissertation.; Madison M. Collins, Kyle A. Glose, Kyler B. Pallister, Tyler K. Pallister and Jovanka M. Voyich were co-authors of the article, 'Uncovering the executioner: disruption of pulmonary surfactant by influenza A triggers Staphylococcus aureus Pneumonia' which is contained within this dissertation.Infection influenza A virus (IAV) leads to increased host susceptibility to secondary bacterial pneumonia. In cases such as these, Staphylococcus aureus (S. aureus) has emerged as the dominant bacterial pathogen associated with severe infection outcomes. S. aureus is a common commensal of the anterior nares and is frequently trafficked into the lower respiratory tract through inhalations, micro-aspirations, and direct mucosal dispersion. Despite recurrent exposure to the lungs and the capacity to cause severe disease, cases of S. aureus pneumonia are rare in immunocompetent hosts. Previous efforts interrogating S. aureus secondary bacterial pneumonia have largely focused on the immunomodulation that occurs during the antecedent influenza infection and have ignored the virulence contributions of the bacterial pathogen. To that end, we developed a murine model of secondary pneumonia to investigate S. aureus pathogenesis following influenza A infection. We identify that secondary bacterial pneumonia by S. aureus is dependent on the activation of the two-component regulatory system (TCS) SaeR/S. Further, studies demonstrated that in the absence of IAV infection the healthy lung environment suppresses virulence gene expression. Characterization of the lung environment revealed that the lipid constituents of pulmonary surfactant suppress S. aureus virulence production. Our data provide a model of secondary bacterial pneumonia wherein infection with IAV significantly reduces surfactant lipid concentrations within the lungs. The reduction of pulmonary surfactant lipids leads to a loss of S. aureus virulence suppression and rapid activation of the major virulence regulator saeR/S. Taken together, these data provide a strong rational for the low incidence of primary S. aureus pneumonia and the increased severity of S. aureus pneumonia following antecedent influenza A infection. Furthermore, these data highlight possible pulmonary surfactant replacement therapies that may significantly alleviate secondary bacterial pneumonia morbidity and mortality.Item Adaptive immunity to Chlamydia pneumoniae respiratory infection(Montana State University - Bozeman, College of Agriculture, 2000) Day, Thomas GordonItem The alveolar macrophage in pulmonary infection : a comparison of permissiveness to infection with an obligate and a facultative intracellular pathogen(Montana State University - Bozeman, College of Agriculture, 2013) Calverley, Matthew David; Chairperson, Graduate Committee: Allen G. Harmsen; Allen G. Harmsen, Sara Erickson, and Amanda J. Read were co-authors of the article, 'Resident alveolar macrophages are susceptible to and permissive of Coxiella burnetii infection' in the journal 'PLoS ONE' which is contained within this thesis.; Robert A. Cramer and Allen G. Harmsen were co-authors of the article, 'The facultative intracellular pathogen Cryptococcus neoformans proliferates primarily extracellularly early in in vivo infection' submitted to the journal 'mBio' which is contained within this thesis.The lung must mount an effective immune response to pathogenic challenge while controlling attendant tissue damage. Central to this co-ordination are the immunomodulatory effects exerted by the pulmonary environment on the local alveolar macrophages (AMs). Moreover, intracellular pathogens are known to exploit the host immune system. For this reason, we hypothesized that the resident AM would comprise a vulnerable population of cells capable of being exploited by intracellular pathogens. To test this hypothesis, we investigated the role of the AM during pulmonary infection with either the obligate intracellular bacterium Coxiella burnetii or the facultative intracellular fungus Cryptococcus neoformans. We showed [1] that resident AM are indeed the cell-type most susceptible to infection with C. burnetii. These resident AM remain infected up to twelve days, serving as a permissive niche that supports bacterial survival. Additionally, a subset of infected AMs underwent a characteristic phenotypic change in response to infection, resulting in an increased expression of surface integrin CD11b and continued expression of surface integrin CD11c. We conclude that C. burnetii is capable of exploiting the pulmonary environmental effects on the resident AM allowing for exploitation of the AM as a susceptible and permissive niche for infection. In the context of C. neoformans infection, we found that only a restricted population of C. neoformans replicated in AMs. The majority of C. neoformans that replicated in vivo did so extracellularly and the extent of extracellular replication exceeded intracellular replication of the yeast. In fact, the majority of intracellular fungal load in AMs at 48 hours post-infection was attributable to the uptake of extracellular C. neoformans from 24 to 48 hours post-infection. Thus, unlike C. burnetii, C. neoformans does not appear to exploit the pulmonary environmental effects on the resident AM during establishment of infection. Through the identification of the AM as a susceptible and permissive niche for C. burnetii infection and the finding that C. neoformans replicates primarily extracellularly during early pulmonary infection, we have both filled a deficiency in the previous knowledge base and set the stage for future studies into the induction of subsequent adaptive immune responses during these varied infections.