Conditional M. tuberculosis knockdown mutants in mice with human-like pathology

About This Grant

Mouse models are critical for studying the pathogenesis of tuberculosis (TB) and for assessing new drug targets, treatment regimens and vaccine strategies. Standard C57BL/6 and BALB/c mouse models do not develop the pathology observed in humans, such as necrotic, hypoxic and caseating granulomas. In contrast C3HeB/FeJ mice develop a spectrum of TB lesions that more closely resemble human granulomas and other pathological environments. However, this mouse strain has rarely been utilized to investigate Mycobacterium tuberculosis (Mtb) mutants or paucibacillary Mtb infections that mimic latent infections in humans. We propose to analyze conditional knockdown mutants for thioredoxin reductase (TrxB2) and biotin protein ligase (BPL) in C3HeB/FeJ mice. We will determine the ability of conditional Mtb mutants to establish infection in mice with human-like pathological environments and determine the impact of TrxB2 and BPL depletion in different lesion types. We will establish genetic latency models in C3HeB/FeJ mice and test the hypothesis that a larger percentage of mice with caseous necrotic pulmonary granulomas will harbor latent bacilli that cause TB relapse than observed in C57BL/6 mice.