Timeline to the stages of tuberculosis disease progression

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University of Cape 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.

M. tuberculosis infects about a quarter of all people worldwide. Some infected people remain healthy, but 5% to 15% 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, Associate Professor Thomas Scriba of the South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and division of immunology, department of pathology, University of Cape Town, 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 signalling 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 analysed 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.

Abstract
Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 cells 3 weeks postvaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis.

Authors
Thomas J Scriba, Adam Penn-Nicholson, Smitha Shankar, Tom Hraha, Ethan G Thompson, David Sterling, Elisa Nemes, Fatoumatta Darboe, Sara Suliman, Lynn M Amon, Hassan Mahomed, Mzwandile Erasmus, Wendy Whatney, John L Johnson, W Henry Boom, Mark Hatherill, Joe Valvo, Mary Ann De Groote, Urs A Ochsner, Alan Aderem, Willem A Hanekom, Daniel E Zak

South African Tuberculosis Vaccine Initiative material
PLOS Pathogens abstract
file:///C:/Users/Sally%20Fowler%20Delport/AppData/Local/Packages/Microsoft.MicrosoftEdge_8wekyb3d8bbwe/TempState/Downloads/journal.ppat.1006687.pdf


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