DESIGNER ARRAYS FOR DEFINED MUTANT ANALYSIS IN A MACAQUE MODEL OF TUBERCULOSIS

Tulane University Of Louisiana, New Orleans LA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The basic mechanisms employed by M. tuberculosis (Mtb) to successfully infect and persist in mammalian lungs are poorly understood. DeADMAn (Designer Arrays for Defined Mutant Analysis) represents a high-throughput approach for subtractive identification of mutants attenuated for survival in animal tissues. Monkeys infected with Mtb represent an excellent model of TB - they exhibit pathology remarkably similar to humans and develop human-like latent TB. We conducted experiments with the DeADMAn technology in monkeys. We identified over 100 genes, mutants in which were attenuated for in-vivo growth in macaque lungs, in this model of acute TB. Some of these genes have previously been shown to be implicated to have a role during growth in macrophage or mouse studies. We also identified numerous novel genes with no previous report of being important for in-vivo growth. These include the cadI, cobL, drrA, lpqP, fadD21, cycA, yrbE3B, lipU, lprO, lppV, mce1, mce3 and mce4 genes. We propose to study these differences using the identical mutant screen, but in a model of latent disease, during co-infection with SIV, during dissemination and following BCG vaccination. These studies will shed light on the differences in virulence-mechanisms employed by tubercle bacilli for infecting various animal models.