Theses and Dissertations at Montana State University (MSU)
Permanent URI for this collectionhttps://scholarworks.montana.edu/handle/1/733
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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 The role of SaeR/S in secondary Staphylococcus aureus Pneumonia(Montana State University - Bozeman, College of Agriculture, 2016) Hisey, Bennett Stephen; Chairperson, Graduate Committee: Jovanka Voyich-Kane; Timothy R Borgogna, Kyler B. Pallister, Eli W. Sward, Fermin E. Guerra and Jovanka M Voyich were co-authors of the article, 'The role of SaeR/S in secondary Staphylococcus aureus pneumonia' submitted to the journal 'Journal of infectious diseases' which is contained within this thesis.Methicillin?resistant Staphylococcus aureus (MRSA) is a Gram?positive pathogen capable of causing diverse disease in humans. MRSA precisely controls virulence factor expression via the SaeR/S two?component gene regulatory system. While much is known about SaeR/S regulation patterns during skin infection, less is understood about the role it plays in the pulmonary environment during secondary staphylococcal pneumonia. Using an isogenic deletion mutant in pulsed field gel electrophoresis type USA300 (strain LAC) of the saeR/S two?component gene regulatory system we examined its role in mouse models of pathogenesis involving primary infection with influenza strain A/WSN/33 followed by USA300 infection. Results demonstrate SaeR/S contributes significantly to mortality during pneumonia following influenza A infection. Reverse transcription PCR and QuantiGene 2.0 assays revealed differences in both transcription of components of SaeR/S as well as virulence factors under SaeR/S control. Primary Influenza infection was seen to up regulate expression of virulence factors under control due to antecedent influenza A infection. These data underscore the importance of pathogen contribution to the pathogenesis of secondary pneumonia.Item The role of mast cells during influenza A virus infection(Montana State University - Bozeman, College of Letters & Sciences, 2015) Graham, Amy Catherine; Chairperson, Graduate Committee: Josh Obar; Rachel M. Temple and Joshua J. Obar were co-authors of the article, 'Mast cells and influenza A virus: association with allergic responses and beyond' submitted to the journal 'Frontiers in immunology' which is contained within this thesis.; Kimberly M. Hilmer, Julianne M. Zickovich and Joshua J. Obar were co-authors of the article, 'Inflammatory response of mast cells during influenza A virus infection is mediated by active infection and RIG-I signaling' in the journal 'The journal of immunology' which is contained within this thesis.; Julianne M. Zickovich, Kimberly M. Hilmer and Joshua J. Obar were co-authors of the article, 'Differential role of influenza A virus binding preference in mast cell activation' submitted to the journal 'The journal of virology' which is contained within this thesis.Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections and causes ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought to be the result of significant pulmonary immunopathology from the inflammatory response rather than viral replication. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. Additionally, recruitment of neutrophils and macrophages is required for optimal clearance of IAV. Recent global analysis of lungs from mice infected with highly pathological IAV strains demonstrated enrichment of a mast cell transcriptional response, but the role of mast cells during severe pulmonary viral infections has been under studied. We found that A/WSN/33 causes significant immunopathology in C57Bl/6 mice and viral-induced pathology is mast cell-dependent. A/WSN/33 is able to directly activate bone marrow cultured mast cells (BMCMC) to produce histamine, leukotrienes, inflammatory cytokines, and anti-viral chemokines. Moreover, human H1N1, H3N2, and influenza B virus isolates can activate murine BMCMC in vitro suggesting this pathway could play a role during human infections. BMCMC activation requires infection of mast cells by IAV, which is dependent on the viral hemagglutinin specificity for alpha2,6-linked sialic acids. Cytokine and chemokine production from BMCMC occurs in a RIG-I-dependent fashion that requires the de novo production of vRNA. Conversely, degranulation occurs through a RIG-I-independent mechanism. Reconstitution of mast cell deficient mice with RIG-I -/- BMCMC generates lung pathology similar to wild-type BMCMC, suggesting that mast cell degranulation, rather than production of cytokines, causes A/WSN/33 induced lung pathology. Using recombinant A/WSN/33 strains, we found an association between binding of the A/WSN/33 hemagglutinin to alpha2,6-sialic acids and subsequent interactions with neuraminidase is important for degranulation. Thus, we have identified a unique inflammatory cascade that could be therapeutically targeted to limit morbidity following infection with IAV.