Francisella tularensis is a highly infectious gram-negative coccobacillus that causes thezoonosis tularemia and is a Category A agent. F. tularensis survives and replicates withinmacrophages, a phenotype that correlates with virulence, yet little is understood about themolecular basis of its pathogenesis. The long-term goal of this project is to understand how F.tularensis subverts host defenses.
This aim will fundamentally interface with the goal of thisProgram Project, which is to understand how diverse intracellular pathogens such asMycobacterium tuberculosis, Listeria monocytogenes and Histoplasma capsulatum manipulatehost innate responses. We hypothesize that a comparative analysis of the macrophagetranscriptional responses to these four intracellular pathogens will be a very powerful means ofdissecting and understanding the results of our microarray experiments.We hypothesize that F. tularensis produces gene products that alter the trafficking and perhapsacidification of the initial bacterial phagosome, thereby allowing bacteria to escape into thecytoplasm where it can survive and replicate. The objective of this proposal is to use moleculargenetic approaches to uncover F. tularensis molecules that are required for intracellular survivaland growth. In a parallel approach, DNA microarrays will be used to characterize themacrophage response to F. tularensis and to test our hypothesis that this pathogen will induce acytosolic pathway of host gene expression similar to L. monocytogenes.
Our specific aims are to 1) identify F. tularensis genes that are expressed inside of macrophages and constructmutants defective in macrophage replication; 2) analyze the intracellular replication andtrafficking of F. tularensis; and 3) characterize the macrophage transcriptional response to F.tularensis. These studies will identify regulatory circuits in host cells that are manipulated by F.tularensis and other key intracellular pathogens relevant to biodefense.
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