Worldwide, tuberculosis (TB) is the leading cause of death from infectious disease. One key to the disease’s persistence is the formation of granulomas — clusters of immune cells that wall off the bacterium inside the body. These structures help keep the bacteria from spreading but can also protect them from antibiotics.
This protection comes at a price; at the center of many granulomas is a core of dead tissue where nutrients are scarce, and the bacteria struggle to survive. This necrotic core is important for understanding how TB works, but it’s hard to study in many laboratory models.
Now, thanks to a new laboratory method and a multi-institutional collaboration, researchers at Duke University School of Medicine and UNC-Chapel Hill have pinpointed several groups of bacterial genes that are turned on only inside granulomas. These genes help the bacteria gather essential minerals, protect themselves from harmful molecules, and adapt their metabolism to low-nutrient, stressful conditions.
"We found evidence that the genes we identified as being activated in granulomas have been selected for in evolution over the last few thousand years." — David Tobin, PhD
“We found evidence that the genes we identified as being activated in granulomas have been selected for in evolution over the last few thousand years,” said David Tobin, PhD, a senior author of the study and professor of molecular genetics and microbiology and integrative immunobiology. “This points to a whole new class of bacterial genes that seem to play a role in the key host-pathogen interface.”
Duke postdoctoral fellow Gopinath Viswanathan, PhD, figured out for the first time how to measure bacterial gene activity directly within tuberculous granulomas by combining high-resolution imaging with a new protocol that enriches bacterial RNA. He did this in adult zebrafish that naturally form TB-like granulomas with these necrotic (dead tissue) centers.
These findings reveal what the bacteria are doing to survive in this stressful environment, both when certain immune cells called neutrophils are present and when they are not.
Then the team partnered with a lab at UNC-Chapel Hill led by Qingyun Liu, PhD, to examine the genomes of over 50,000 Mycobacterium tuberculosis strains from around the world. The researchers found signs that these survival-related genes have been shaped by evolution in human populations, suggesting they play an important role in long-term infection.
Together, these findings reveal how the immune system shapes the evolution and persistence of the TB bacterium and point the way toward new strategies to combat this global killer.
Funding: The National Institutes of Health.