Theses and Dissertations at Montana State University (MSU)
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Item The roles of interleukin-1 and leukotriene-B4 in the innate immune response to pulmonary Aspergillus fumigatus infection(Montana State University - Bozeman, College of Letters & Science, 2017) Caffrey-Carr, Alayna Katherine; Chairperson, Graduate Committee: Mark T. Quinn; Margaret M. Lehmann, Julianne M. Zickovich, Vanessa Espinosa, Kelly M. Shepardson, Christopher P. Watschke, Kimberly M. Hilmer, Arsa Thammahong, Bridget M. Barker, Amariliz Rivera, Robert A. Cramer and Joshua J. Obar were co-authors of the article, 'IL-1A signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge' in the journal 'PLoS pathogens' which is contained within this thesis.; Joshua J. Obar was a co-author of the article, 'Alarmin(G) the innate immune system to invasive fungal infections' in the journal 'Current opinion in microbiology' which is contained within this thesis.; Caitlin H. Kowalski, Sarah R. Beattie, Nate A. Blaseg, Chanell R. Upshaw, Arsa Thammahong, Hannah E. Lust, Yi-Wei Tang, Tobias M. Hohl, Robert A. Cramer, Joshua J. Obar were co-authors of the article, 'IL-1A signaling is critical for resistance against highly virulent Aspergillus fumigatus strains' submitted to the journal 'Infection and Immunity' which is contained within this thesis.; Kimberly M. Hilmer and Joshua J. Obar were co-authors of the article, 'Host-derived leukotriene B4 is critical for resistance against invasive pulmonary Aspergillosis' submitted to the journal 'Microbes and Infection Short Communication' which is contained within this thesis.Aspergillus fumigatus is a ubiquitous environmental mold, and even though most individuals are regularly exposed to fungal spores, clinical invasive disease is a rare manifestation. However, in the growing population of individuals with weakened immune systems, for example due to prolonged corticosteroid treatment or chemotherapeutic interventions, A. fumigatus exposure can cause severe, invasive aspergillosis (IA). Overall, invasive fungal infections are estimated to kill at least 1.5 million people annually (Brown et al. 2012), with IA being the most common and deadly invasive respiratory fungal infection. Thus, it is critical to better understand the host-pathogen interactions after A. fumigatus exposure in order to develop novel treatment options which harness the power of the host's immune response. Defining key immunological events that are needed for the prevention of Aspergillus growth within the pulmonary environment of immune competent individuals is an essential step toward a better understanding of how the immune response is altered within the immune compromised populations that are at risk of developing IA. Utilizing an immune competent murine model of IA, we have shown that signaling through both the Interleukin-1 receptor, type I (IL-1RI) and the Leukotriene B4 receptor (BLT1) are both critical pathways for host resistance against IA through timely neutrophil recruitment which ultimately control fungal germination. More recently, we have found that different environmental and clinical strains of A. fumigatus lead to different inflammatory profiles as well as different disease pathology. Strains that are able to germinate within the lung environment are more virulent, and lead to enhanced lung damage, vascular leakage and inflammation. Furthermore, the more virulent strains induce neutrophil recruitment and subsequent fungal clearance that is dependent on the alarmin IL-1alpha, while clearance of the less virulent strains are independent of IL-1alpha signaling. With this research we will better understand the fungal component(s) that are important in virulence determination, which immune pathways are contributing to the different disease pathologies observed, as well as understand the mechanism through which a healthy immune system can resist A. fumigatus exposure on a daily basis.