Researchers have uncovered a sequence of biological processes that occur in humans infected with the bacterium Mycobacterium tuberculosis as the infection progresses to pulmonary tuberculosis, according to new research published in PLOS Pathogens.
M. tuberculosis infects about a quarter of all people worldwide. Some infected people remain healthy, but five to 15 percent eventually develop active tuberculosis disease, which can be deadly. The most common form of the disease occurs in the lungs and is known as pulmonary tuberculosis. Pulmonary tuberculosis can be cured, but little is known about how it develops from the initial infection.
To better understand the mechanisms that underlie development of tuberculosis, Thomas Scriba of the University of Cape Town, South Africa, and colleagues followed 150 adolescents infected with M. tuberculosis for several years. 106 of the study participants remained healthy, but 44 went on to develop pulmonary tuberculosis within a few years of initial infection.
During the study period, the researchers took regular measurements to monitor and compare immune system activity between individuals who remained healthy and those who eventually fell ill. They found that some differences were detectable as early as one to two years before diagnosis, while some were only detectable just before active disease began.
Eighteen months before diagnosis, the researchers found, individuals had elevated activity of immune system signaling molecules known as interferons, which aid in fighting infection. They also had elevated activity of the complement system, another immune system component. In the days just before diagnosis, additional immune changes occurred, including increased activity of white blood cells.
The scientists also analyzed which genes were expressed in T cells (a type of white blood cell) purified from study participants' blood. They found that certain genes associated with T cells' response to infection were suppressed in those who later developed pulmonary tuberculosis.
Overall, these findings lay out a clearer timeline of biological events that occur along the path from infection to disease. With further research, this knowledge could aid development of new strategies for diagnosis, vaccination, and treatment.
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Citation: Scriba TJ, Penn-Nicholson A, Shankar S, Hraha T, Thompson EG, Sterling D, et al. (2017) Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease. PLoS Pathog 13(11): e1006687. https:/
Image Caption: Progression from quiescent Mycobacterium tuberculosis infection, via incipient and subclinical disease, to active pulmonary tuberculosis disease in humans.
Image Credit: Scriba TJ, et al (2017)
Funding: This work was supported by grants from the Bill and Melinda Gates Foundation (BMGF) Global Health grants OPP1021972 and OPP1091720 and the National Institutes of Health (RO1-AI087915 and U19-AI106761). The ACS study was also supported by Aeras and BMGF GC6-74 (grant 37772) and BMGF GC 12 (grant 37885) for QuantiFERON testing. The Adult BCG Revaccination trial was supported by Contract No.NO1-AI95383 and HHSN266200700022C/NO1-AI-70022 from the US National Institutes of Health. APN and SS were supported by Postdoctoral Research Awards from The Carnegie Corporation of New York. APN was also supported by The Claude Leon Foundation and the Columbia University-Southern African Fogarty AIDS International Training and Research Program (AITRP) through the Fogarty International Center, National Institutes of Health (grant # 5 D43 TW000231). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: TJS, APN, EGT, AA, WAH, and DEZ are co-inventors on a patent of the 16-gene transcriptomic correlate of risk of TB. DS, MAdG, TH and UAO are current or former employees of or hold stock options in SomaLogic, Inc. and received funding from the Bill & Melinda Gates Foundation (OPP1091720). This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials. All other authors have declared that no competing interests exist.