Theses and Dissertations at Montana State University (MSU)
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Item The regulation and function of integrin alphaE (CD103) in human dendritic cells(Montana State University - Bozeman, College of Letters & Science, 2019) Roe, Mandi Marie; Chairperson, Graduate Committee: Diane Bimczok; Steve Swain, T. Andrew Sebrell, Marisa A. Sewell, Madison M. Collins, Brian A Perrino, Philip D. Smith, Lesley E. Smythies and Diane Bimczok were co-authors of the article, 'Differential regulation of CD103 (alphaE integrin) expression in human dendritic cells by retinoic acid and toll-like receptor ligands' in the journal 'Journal of leukocyte biology' which is contained within this thesis.; Steve Swain, Marziah Hashimi, Krista M. Woo and Diane Bimczok were co-authors of the article, 'A novel role of P38 MAPK signaling and NFAT in the RA-induced expression of CD103 in human dendritic cells' submitted to the journal 'Immunology' which is contained within this thesis.; Dissertation contains an article of which Mandi Marie Roe is not the main author.Retinoic acid (RA) is a master regulator of cellular signaling and function as well as an important mediator of immune development and maintenance. CD103 is a marker that is used to distinguish functional subsets of mucosal DCs. Despite the use of CD103 as a DC marker, the RA-induced pathway leading to CD103 expression is yet unknown. In addition, the function of DC CD103 has not been fully elucidated. In this dissertation research, we evaluated the regulation of CD103 expression on human DCs and investigated the function of DC CD103. We first found that CD103 expression is driven by RA and that CD103 is found in intracellular pockets in human DCs. However, the RA-induced increase of CD103 was abrogated upon stimulation of DCs with TLR ligands. To elucidate the RA-induced pathway of CD103 expression, we established the dependence on p38 MAPK signaling and NFAT through the use of specific inhibitors. Studies with RARalpha siRNA and the use of RAR-specific agonists show that CD103 expression is dependent on RARalpha signaling. To investigate further the intracellular CD103 expression, we demonstrated that CD103 was co-localized with endosomal markers and was actively internalized over time in DCs, suggesting CD103 undergoes endosomal recycling. Based upon imaging of gastric tissue showing CD103^+ DCs are most often within the gastric epithelial layer, we sought to understand the role of CD103 in DC adhesion. We investigated whether CD103 is involved in adhesion of DCs to the epithelium by co-culturing the DCs with HT-29 cells, which express E-cadherin on the entire cell surface. Interestingly, we found that CD103 was not a main driver of DC-epithelial adhesion, but that DC binding to the gastrointestinal epithelium was mediated by the interactions between DC E-cadherin and E-cadherin on the HT-29 cells. In summary, this research has contributed to the understanding of CD103 expression and function on human DCs. CD103 plays a minor role in the adhesion of DCs to the gastrointestinal mucosa, despite CD103^+ DCs close proximity to the gastric epithelium. RA drives the expression of CD103 on DCs mediated through RARalpha and p38 MAPK signaling and NFAT.Item In vivo effect of mouse peritoneal cells on Candida albicans(Montana State University - Bozeman, College of Agriculture, 1979) Poor, Anne HollyItem Evaluation of the cell-mediated immune response to bovine respiratory syncytial virus infection in cattle(Montana State University - Bozeman, College of Agriculture, 1979) Field, Emery WaineItem Induction of cell-mediated immune responses with effector functions by antigens of Tritrichomonas foetus(Montana State University - Bozeman, College of Agriculture, 2001) Voyich, Jovanka Marija (Vujadinovich)Item Molecular interaction of human neutrophil NADPH oxidase proteins(Montana State University - Bozeman, College of Agriculture, 1996) DeLeo, Frank RobertItem Humoral and cellular aspects of immunity to Trypanosoma musculi in mice(Montana State University - Bozeman, College of Agriculture, 1979) Brooks, Bradford OldhamItem Effects of antibodies to membrane antigens on in vitro immune responses(Montana State University - Bozeman, College of Agriculture, 1983) Harp, James AlanItem Identification of novel virulence factors and mechanisms of pathogenesis from the sexually transmitted protozoan Tritrichomonas foetus(Montana State University - Bozeman, College of Agriculture, 2006) Higgins, Melanie Rae; Chairperson, Graduate Committee: Allen G. Harmsen.Tritrichomonas foetus (T. foetus) is the cause of trichomoniasis in cattle. Little is known regarding the basis of virulence in this parasite. Early host-parasite interactions most likely affect the ability of the parasite to colonize the female reproductive tract. These early interactions shape the course of disease and ultimately control the outcome of pathogenesis. The aim of the studies herein is to provide insight into the factors that alter the progression of trichomoniasis. We examined how environmental stress and estradiol treatment affect pathogenesis of trichomoniasis. Acute T. foetus infection in normal mice resulted in facile colonization of the reproductive tract with little epithelial damage, inflammation, or cytokine expression. Infection in estradiol-treated or stressed mice resulted in increased tissue damage, inflammation, and inflammatory cytokine expression. However, estradiol-treatment or stress did not result in enhanced T. foetus colonization within the reproductive tract. Since T. foetus has been associated with heavy neutrophil and macrophage accumulation in severe disease states, an additional goal was to examine the role of the innate immune system in the colonization of T. foetus within the murine reproductive tract. Mice depleted of neutrophils were more susceptible to infection than mock-depleted controls. Additionally, mice with deficiencies in RNS production had substantially larger parasite burdens than mice with the ability to generate RNS, whereas mice with the ability to generate ROS were equally able to control dissemination of T. foetus throughout the reproductive tract, compared to wild-type controls. Lastly, we examined the relationship between T. foetus and epithelial cell interactions to trichomonad virulence. Investigation of host-parasite interactions revealed that T. foetus exhibited increased adhesion and cytotoxicity towards host cells. In addition, a secreted cytoactive factor termed CDF was isolated and purified from activated parasites. This 30 kDa cysteine protease caused rounding and detachment of target cells in addition to inducing apoptosis and 100% cell death by 72 hours of exposure to target cells. These results support our hypothesis that initial parasite/host cell interactions affect trichomonad virulence.