Graduate Thesis Or Dissertation


Mechanisms for the interaction of environmental mycobacteria with host cells Public Deposited

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  • Environmental mycobacteria are important opportunistic pathogens for many hosts, including humans, cattle, and fish. Two well-studied species are Mycobacterium avium subsp. avium, a significant cause of disseminated bacterial disease in patients with AIDS, and Mycobacterium avium subsp. paratuberculosis, the cause of Johne’s disease in cattle. Many other species that are considerable sources of infections in fish, such as Mycobacterium chelonae and Mycobacterium marinum, also have zoonotic potential. To gain knowledge about the invasion of epithelial cells by environmental mycobacteria, selected genes and proteins involved in the uptake of M. avium by HEp-2 cells were analyzed by a variety of methods. Two transcriptional regulators (MAV_3679 and MAV_5138) were identified as being involved in invasion. A mycobacterial protein (CipA) with an amino acid sequence suggestive of an ability to be a part of the scaffolding complex that forms during cell signaling leading to actin polymerization was found to putatively interact with host cell Cdc42. Fusion of CipA to GFP, expressed in Mycobacterium smegmatis, revealed that CipA localizes to a structure on the surface of bacteria approaching HEp-2 cells. To establish whether species of environmental mycobacteria isolated from different hosts use similar mechanisms to M. avium for interaction with the mucosa, and for survival in macrophages, assays to determine invasion and replication were performed in different cell types, and a custom DNA microarray containing probes for known mycobacterial virulence determinants was developed. Bacteria cultured from macrophages indicated differences between the ability of M. avium and other environmental species to replicate in human, mouse, and carp cell lines. Hybridization of genomic DNA isolated from EM species against the sequenced MAC104 strain of M. avium showed that there are genes and regions of the chromosome absent from a subset of those species that may be important in determining host specificity and the in differences in virulence observed in vitro and in vivo. Finally, the intestinal epithelium was determined to be the primary route of infection for mycobacteria in zebrafish, similar to M. avium infection in humans. M. avium does not infect zebrafish, but the comparative virulence and genomics of some species isolated from fish suggest that they could be used as a surrogate model to continue progress in understanding the interaction between environmental mycobacteria and epithelial cells.
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