In 1884, Robert Koch discovered that Mycobacterium tuberculosis is the causative agent of human tuberculosis. Quite alarmingly, a hundred and 33 years later (2017), TB still remains a global health problem, with an estimated 2 billion people reported to harbor TB infection in a latent form and an annual mortality rate approaching 2 million deaths. Latent TB and reactivation of infection into symptomatic disease represents a formidable hurdle for elimination of TB.
Scientists at the Albert Einstein College of Medicine and colleagues uncover how the TB bacterium deals with stress likely imposed by the human immune system to cause latency. The findings are published in the journal Plos Pathogens. "Mycobacterium tuberculosis universal stress protein Rv2623 interacts with the putative ATP binding cassette (ABC) transporter Rv1747 to regulate Mycobacterial growth."
In their publication the authors show that the TB bacterium "self-medicates" in response to stress by over-producing a protein known as Rv2623. Further studies show that Rv2623 controls the growth of the TB bacterium by regulating the transportation of molecules known as PIMs (phosphatidyl-myo-inositol mannosides) required for building the bacterium's cell wall.
Rv2623 serves as an intermediate for transferring stress signals to the transporter (Rv1747) of PIMs by interacting and negatively regulating PIM transporter function through a process known as phosphorylation. When the PIM transporter is phosphorylated, the PIM molecules are not transported to the cell wall construction site and the TB bacterium stops growing-but remains viable-this process is believed to enable the TB bacterium to persist within the human lung.
The authors previously discovered that the TB bacteria without the PIM transporter (Rv1747) cannot survive during infection while in contrast, the TB bacteria that lack the stress protein Rv2623 over-express the PIM molecules in their cell wall.
Collectively, the data presented by the authors demonstrate how the TB bacterium deals with stress by entering latency and suggest that understanding the mechanisms that regulate TB latency will guide the design of better anti-TB drugs.
This work represents great promise in the fight against TB.