Friday, May 9, 2025
5/9/2025
Assessing the Mycobacterium tuberculosis carriage state - Project Summary It is hypothesized that Mycobacterium tuberculosis (Mtb), the primary agent of human tuberculosis (TB) has been with the human population for more than 12,000 years. Although there are nearly 9 million new cases of TB each year, the vast majority of individuals who come into contact with this organism appear to clear it with no ill effects. The mechanisms employed during this ‘clearance’ process are generally unknown. In high-exposure TB epidemiologic settings, a small percentage of contacts go on to develop sputum culture-positive active disease with all symptomology, histopathology and immune responses that characterize TB; these individuals are assumed to be responsible for the subsequent TB transmission that occurs. A larger percentage of contacts become tuberculin skin test (TST)-positive but remain culture negative (latent disease); these individuals likely do not transmit to contacts while in the latent stage. Thus, it is assumed that a majority of TST-negative individuals have not been exposed to Mtb, or have cleared any bacilli to which they may have been exposed without inducing immunity. However, these TST-negative contacts rarely have their upper respiratory tracts (URT) cultured for Mtb. Major human respiratory bacterial pathogens such as Streptococcus pneumoniae and Haemophilus influenzae utilize an URT carriage state in which the bacteria attach to the local epithelium, replicate, and transmit to other persons, but do not damage the host cells, cause disease in this location or induce more than a very mild local inflammation; ultimately, these commensal bacteria can clear or they can disseminate to sterile areas of the body including the lower lung and brain and cause disease. Infant humans are URT colonized at higher rates than adults with correspondingly higher rates of meningitis. Importantly, some vaccines can clear URT colonizing bacteria and thus prevent subsequent disseminated disease states or transmission to naïve contacts. Data from TB studies not originally designed to assess carriage have indirectly demonstrated that Mtb also possesses a URT carriage-like state in humans (and we have demonstrated it in natural transmission studies in ferrets), and if similar to the other respiratory pathogens, understanding this state is critical to ultimately more accurately diagnosing, controlling disease development and transmission and improving vaccine efficacy. We intend to perform a longer-term Mtb URT carriage analyses in asymptomatic adult humans in Kampala, Uganda exposed to active TB cases. Investigators in the field consider Mtb carriage to either not exist, or not be relevant in the case of transmission and development of disease. Preliminary evidence indicates this is not the case. If accurate, this may be a significant missing component in our efforts towards developing a comprehensive control strategy for TB.
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