OF THE OVERALL U19 APPLICATION (as provided by applicant): Mycobacterium tuberculosis (Mtb) is one of the world's most successful pathogens. WHO estimates that about one third of the world's population has a positive skin test that reflects a long-term adaptive immune response to Mtb antigens. These individuals are considered to have actual or potential latent Mtb infection (LTBl). Among them, a minority that cannot be identified prospectively will develop reactivation tuberculosis (TB) despite having apparently normal immunity. Active TB can be contagious both to those who were previously unexposed and those with LTBl and is usually lethal if untreated. Adequate numbers of CD4 T cells, tumor necrosis factor alpha (TNF?), and interferon-gamma (IFN?) are validated determinants of control of primary TB, but the vast majority of HIV negative patients with reactivation TB do not have defined defects in these pathways. The ability of Mtb to remain latent within the human host, and the related failure of the human immune system to sterilize Mtb in latently infected individuals, are poorly understood. Antimicrobial therapy for active infection by drug-sensitive Mtb is effective, but current drugs must be given for 6 months to achieve relapse-free cure rates of >95%. The necessity for this prolonged duration of therapy is attributable to the ability of genetically drug-sensitive Mtb to adopt a phenotypically drug-tolerant, persistent state in which it is not readily sterilized by current drugs. Despite substantal efforts to understand these two critical features of Mtb infection-latency and persistence-fundamental questions remain about the genetic, immunologic, and microbiologic contributors to both. We seek to close this knowledge gap through a Tuberculosis Research Unit (TBRU) that unites investigators at Weill Cornell Medical College (WCMC), Rockefeller University (RU), and Memorial Sloan Kettering Cancer Center (MSKCC), with selected external collaborators, and draws on patients at the WMC-affiliated GHESKIO Centers in Haiti to provide insight into latency and persistence of Mtb during human infection.
This multi-institutional TBRU will deliver new insights into the ability of M. tuberculosis to resist elimination by the human immune system during latency and by antimicrobials during drug treatment for tuberculosis.
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