Mycobacterium tuberculosis (Mtb) is one of the world's most successful pathogens. WHO estimates thatabout one third of the world's population has a positive skin test that reflects a long-term adaptive immuneresponse 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 werepreviously unexposed and those with LTBl and is usually lethal if untreated. Adequate numbers of CD4 Tcells, tumor necrosis factor alpha (TNFα), and interferon-gamma (IFNy) are validated determinants of controlof primary TB, but the vast majority of HIV negative patients with reactivation TB do not have defined defectsin these pathways. The ability of Mtb to remain latent within the human host, and the related failure of thehuman immune system to sterilize Mtb in latently infected individuals, are poorly understood. Antimicrobialtherapy for active infection by drug-sensitive Mtb is effective, but current drugs must be given for 6 months toachieve relapse-free cure rates of >95%. The necessity for this prolonged duration of therapy is attributableto the ability of genetically drug-sensitive Mtb to adopt a phenotypically drug-tolerant, persistent state inwhich it is not readily sterilized by current drugs. Despite substantial efforts to understand these two criticalfeatures 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 aTuberculosis Research Unit (TBRU) that unites investigators at Weill Cornell Medical College (WCMC),Rockefeller University (RU), and Memorial Sloan Kettering Cancer Center (MSKCC), with selected externalcollaborators, and draws on patients at the WMC-affiliated GHESKIO Centres in Haiti to provide insight intolatency and persistence of Mtb during human infection.
