Contagious Bovine Pleuropneumonia (CBPP), caused by Mycoplasma mycoides mycoides small colony (MmmSC), is a devastating respiratory disease of cattle in Africa, Asia and the Middle East. Little investigation has been done on molecular disease pathogenesis and host response beyond soluble cytokine detection. This study developed and characterized models for three strains of MmmSC of varying severity. Strains used were Gladysdale, Ondangwa and Shawawa. Samples of bronchoalveolar lavage fluid, bronchial biopsy, nasal epithelial cells and blood were obtained prior to and at weekly time points post-infection. Microarray analysis of RNA extracted from samples revealed host cellular pathways and genes important in the pathogenesis of CBPP, including multiple immune system and inflammatory response pathways. A number of pathways whose influence on disease pathogenesis was not immediately clear were also activated, including pathways involved in amino acid synthesis, fat metabolism, and endocrine hormone responses. Microarray results were confirmed with real-time polymerase chain reaction (RT-PCR) of selected genes. Comparative RT-PCR analysis of selected genes between the three strains of MmmSC revealed genes possibly responsible for differential strain virulence, including interleukins 1B, 6, 8, and 18 and the gene nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (NFKBIA). A similar analysis of selected genes between survivors and nonsurvivors of the virulent Gladysdale strain of MmmSC suggested genes involved in survival, including interleukin 8, calmodulin 2 (CALM2), and NFKBIA. Avenues of additional study were identified. Advisors/Committee Members: Adams, L. Garry (advisor), Ficht, Thomas A. (committee member), Geary, Steven J. (committee member), Welsh, C. Jane (committee member), Womack, James (committee member).