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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.Item The role of T200 (CD45) in leukocyte activation and effector cell function(Montana State University - Bozeman, College of Agriculture, 1987) Taffs, Rolf EdmundItem Analysis of human host defense mechanisms against the opportunistic pathogen, Candida albicans, using in vitro model systems(Montana State University - Bozeman, College of Agriculture, 1999) Edens, Heather AmyItem Regulation of leukocyte L-selectin expression(Montana State University - Bozeman, College of Agriculture, 1993) Palecanda, Aiyappa MuthannaItem Demonstration of the leukocyte-endothelial cell adhesion cascade involved in lymphocyte recirculation and neutrophil and lymphocyte localization to sites of inflammation(Montana State University - Bozeman, College of Agriculture, 1994) Bargatze, Robert FrostItem Identification and characterization of a novel transcription factor that regulates NCF2 expression via the TNF-alpha responsive region(Montana State University - Bozeman, College of Agriculture, 2007) Anderson, Mary Cloud Bosworth Ammons; Chairperson, Graduate Committee: Mark T. Quinn.The multicomponent NADPH oxidase is an essential enzyme complex found in professional phagocytic cells that mediates innate immune defence against multiple pathogens through the production of reactive oxygen species. The vital and functionally limiting cytosolic component of the NADPH oxidase, p67 phox, is transcriptionally regulated by TNF-alpha at the TNF-alpha Responsive Region (TRR) in the intragenic region of Neutrophil Cytosolic Factor 2 (NCF2), the gene which codes for p67 phox. The aim of this dissertation is to identify and charaterize the factor(s) that binds the TRR and regulates NCF2 expression in response to TNF-alpha. Using the TRR as bait in a yeast one-hybrid screen, we identified Pleomorphic Adenoma Gene-Like 2 (PLAGL2) as a candidate regulator of NCF2 expression. In vitro and in vivo analysis confirmed that PLAGL2 binds to the TRR in NCF2 and that endogenous PLAGL2 binding is enhanced in the presence of TNF-alpha. Knock-down of endogenous PLAGL2 expression inhibited TNF-alpha-mediated NCF2 expression, p67 phox expression, and subsequent superoxide production. Characterization of PLAGL2 binding to the NCF2 TRR identified the essential core sequence which is recognized by zinc fingers six and seven of PLAGL2. Using PLAGL2 as bait in a yeast two-hybrid screen, we identified ubiquitin protein ligase (E2I), positive cofactor 2 (PC2,) four and a half LIM domain 3 (FHL3), and chromodomain helicase DNA binding protein 3 (CHD3) as putative PLAGL2 binding partners. In vitro and in vivo analysis confirmed that PLAGL2 binds PC2 434-748, FHL3, and CHD3 via interactions mediated through unique and overlapping domains of PLAGL2. In conclusion, we have identified a novel regulator of NCF2 transcription and have further characterized the features of PLAGL2 binding and recognition of the TRR sequence in the intragenic region of NCF2. Finally, through identification of PLAGL2 binding partners, we have begun to determine a model by which PLAGL2 regulates transcription in a context dependent manner.Item Modulation of the plasma membrane domain structure of human neutrophils(Montana State University - Bozeman, College of Letters & Science, 2006) Stie, Jamal Talal; Chairperson, Graduate Committee: Algirdas J. JesaitisEukaryotic cell plasma membranes form an interface between cells and their environment and function to detect and interpret environmental cues. The work described in this dissertation examines the changes that occur in membrane structure during plasma membrane function in human neutrophils and a fungal opportunist. The body of this work examines how circulating neutrophils can remain functionally inactive in the presence of perturbing influences inherent in the blood circulation, and yet rapidly activate upon exposure to proinflammatory agents. It is hypothesized that the regulated modulation of plasma membrane domain structure determines the activation of blood-leukocytes, in vivo. Experimentation is based the isolation of blood-neutrophils in either nonactivated or activated (primed) cellular states using dextran- or gelatin-based preparative methods, respectively. Analysis of plasma membrane cortical components actin, fodrin, ezrin, CD45 and CD43 by sucrose density sedimentation, flow cytometry and indirect immunofluorescence microscopy indicated significant differences in the plasma membrane structure of both neutrophil populations. In nonactivated neutrophils, cortical actin and fodrin were cytosolic, thus indicating the absence of cortical structure in this population.