While the vast majority of the 1.8 billion people infected with the tuberculosis bacterium never experience active disease, an estimated 5 to 15% do develop full-blown infections roughly half of them within 18 months of exposure. It’s a question that has continue to mystify microbiologists, infectious disease specialists and public health experts on the forefront of the fight against tuberculosis; which continue to claim more lives globally than any other infectious pathogen.
Now, a study by scientists from Harvard Medical School, Brigham and Women’s Hospital; the Broad Institute of MIT and Harvard, Socios en Salud in Peru and other institutions offers an answer: Some of the risk for early disease progression is driven by several gene variants, at least one of which controls key immune functions.
Progression to active tuberculosis
Early progression to active tuberculosis disease soon after infection with the bacterium is physiologically different from late onset disease; which develops after years or decades of dormancy, typically as a result of aging or immuno suppression. Scientists have long suspect that immune system factors drive the progression from latent TB infection to overt disease; hypothesizing that people whose immune systems fail to mount a swift defense progress to overt disease soon after infection.
The study, which involve people infect with tuberculosis in Lima, Peru; pinpoints the precise genetic region that interferes with immune control and leads to early progression. In doing so, the research confirms the role of gene mediate immunity in disease development after TB infection. Additionally, the study points to the different genetic basis for early versus late-onset TB; underscoring how fundamentally different the two forms of the disease are.
“The purpose of our study was to characterize genetic differences between people who develop tuberculosis soon after they have infect; also those who do not progress to overt disease,” said study co-senior investigator Megan Murray, professor in the Department of Global Health and Social Medicine in the Blavatnik Institute at Harvard Medical School. “Our results indicate that early TB progression is a highly heritable trait and one that is genetically distinct from tuberculosis reactivation after years of dormancy.”
The function of immune cells
The analysis trace the epicenter of susceptibility to a region on chromosome 3 involve in regulating the expression of ATP1B3, a protein known to influence the function of immune cells called monocytes, which have critical functions in innate immunity ranging from detecting the presence of viral and bacterial invaders to the detection and destruction of defective or infect cells.
“The risk regions that we identify may play a vital role in the immune responses for TB progression; but they may not be the end of the story,” said lead author Yang Luo, a research scientist and instructor in medicine at Harvard Medical School and Brigham and Women’s. Many more DNA regions driving susceptibility to early disease progression; which are likely to be found as the sizes of genetic samples; also relate studies continue to increase, Luo add.
Infections, especially chronic infectious diseases, play out in highly distinct phases; the team saidl also the new study identifies some of the genetic drivers behind one of these phases. “They believe our analysis is the first step on a long journey,” Raychaudhuri said. “A journey toward identifying new ways to intervene at these distinct stages; and also developing strategies that either optimize host immunity or interfere with the pathogen’s fitness.”