Student Theses and Dissertations

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mycobacterium tuberculosis, salmonella typhimurium, macrophages, host-pathogen interactions, tuberculosis


Over centuries of co-existence with their hosts, microbes that are exclusively vertebrate pathogens have evolved mechanisms for manipulation of host cells and evasion of the immune system. Some pathogens dodge the immune response by altering the functions of and hiding within the very cells that should be consuming and digesting them: macrophages. The aim of these studies was to explore the dynamic interactions the host with two microbes that opt to live within the macrophage phagosome: Mycobacterium tuberculosis (Mtb) and Salmonella typhimurium. In order to identify bacterial genes that provide protection against specific host immune pathways, we have developed the strategy of "differential" signature-tagged transposon mutagenesis (STM). By evaluating bacterial mutants for differential virulence in strains of immuno-deficient mice, we identified five enzymes required for in vivo survival in the face of specific immune stresses: four Mtb enzymes essential for growth and rapid lethality in NOS2- deficient mice but not in IFN-y-deficient mice, and one S. typhimurium enzyme that participates in resistance to phagocyte oxidase. The Mtb enzymes suggest novel pathways for countering IFN-y-dependent immune mechanisms other than NOS2. Analysis of the sequence of the S. typhimurium enzyme suggests the existence in prokaryotes of an alternative signaling pathway that complements classical phospho-relay 2-component regulatory systems.


A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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