Understanding the molecular basis of Mycobacterium tuberculosis latency and reactivation.
Major research activities include studying the adaptation of M. tuberculosis to stress conditions believed to be important in the infected human host, as well as the phenomenon of phenotypic tolerance to antibiotics. In particular, the regulatory cascade involved in the mycobacterial stringent response is under active investigation. A systems biology-based approach, including the use of several novel animal models of latency in combination with transcriptional, proteomic, genetic, imaging, and computational techniques, is being used to identify host cytokine networks responsible for immunological control of M. tuberculosis growth, as well as M. tuberculosis regulatory and metabolic pathways required for bacillary growth restriction and reactivation.
The laboratory is also actively involved in preclinical drug screening in physiologically relevant animal models. For example, the guinea pig, which forms necrotic TB lesions histologically resembling its human counterparts, is being used to study the sterilizing activity of novel drugs and drug combinations against persisters, with the ultimate goal of shortening antituberculous chemotherapy.
A third focus of the laboratory is the development of novel molecular assays for the rapid diagnosis of latent TB infection and active TB disease, and for the detection of drug resistance. Specifically, molecular assays using blood, sputum, and urine samples are being investigated with the goal of developing rapid, sensitive, and specific point-of-care tests for TB diagnosis and detection of drug resistance.
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