The lifecycle of M. tuberculosis within the human host is marked by critical transition points between the major phases of infection: Initial infection, latent disease, active tuberculosis, and resolution with antibiotic therapy. Through observation of patients in each of these stages, we have some knowledge about host determinants that maintain each of these stages, such as the need for sufficient CD4 T cells, interferon gamma and tumor necrosis factor alpha in the control of latency. However, the vast majority of HIV negative TB patients do not have defined deficiencies in these immune factors and therefore the host determinants of the heterogeneous ability of TB patients to control M. tuberculosis infection, either in the context of initial infection after exposure, reactivation of latent infection, or relapse-free elimination of M. tuberculosis after antimicrobial therapy, are unknown. To address these knowledge gaps, we have assembled a set of patient cohorts to examine three interrelated host factors that we hypothesize may contribute to the heterogeneity in host control of M. tuberculosis during the transition from uninfected> LTBl and infected>cured. These factors are Mucosal Associated Invariant T (MAIT) cells, whole blood transcriptomic signatures, and stool microbiomic composition. We will initially examine these factors in two cohorts of TB patients: 1) Patients either resistant to initial infection or recently infected from a household contact, a comparison which will yield correlates of innate resistance to infection and 2) Patients undergoing therapy for active pulmonary tuberculosis, either with short course monotherapy or standard multidrug therapy, to determine correlates of clearance of replicating and persister M. tuberculosis. We anticipate that these studies will provide a set of quantitative molecular assays that will both expand our knowledge ofthe heterogeneity of host control of M. tuberculosis infection, and potentially supply biomarkers that will allow identification of patients resistant to infection, destined to reactivate from latency, or to relapse after antimicrobial therapy.
This project will examine factors that determine the resistance of patients to different forms of infection by M. tuberculosis. These studies will clarify why some patients control this infection effectively, while some do not, and may provide biomarkers that will allow us to predict which patients will develop illness or respond to antibiotic therapy.
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