Mycobacterium tuberculosis, the bacterial strain that causes tuberculosis (TB), infects almost 1.7 billion individuals, or a quarter of the world’s population. Scientists have been working on an effective vaccination for years, but current TB vaccines only provide limited protection.
Researchers from Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), the Ragon Institute at MGH, MIT, and Harvard, as well as the Harvard T.H. Chan School of Public Health (Harvard Chan), have identified beneficial and unhelpful parts of the immune response that influence whether the body can keep TB infections under control.
The findings, which were published in the journal Immunity, could aid in the development of more effective vaccination.
Despite the fact that the immune system can generally keep M. tuberculosis infections under control so that patients do not develop symptoms, there were more than 10 million active cases and 1.6 million TB-related fatalities in 2017.
The body creates granulomas, microscopic clusters of immune cells, and other tissue-resident cells, in reaction to active infection, which primarily assaults the lungs.
With TB, the immune response is pretty good but not great, and until recently, the field has tackled that problem with very rudimentary tools. This collaboration is bringing the very best tools and the very best minds to bear on a really hard, really important problem that most of the world ignores because it primarily impacts the global poor.
Sarah Fortune
Immune activity enhances bacterial clearance in some granulomas, whereas germs persist and develop in others. Even in the same person, various granuloma responses might be detected.
“Identifying which cellular and molecular features associate with bacterial control could potentially point to new therapeutic and prophylactic strategies for TB,” says co-senior author Alex K. Shalek, Ph.D., a principal investigator who conducts research through the Ragon Institute of MGH, MIT, and Harvard as well as through the Institute for Medical Engineering and Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research at MIT and the Broad Institute of MIT and Harvard.
To do so, Shalek and his colleagues used single-cell profiling tools and collaborated with scientists from JoAnne Flynn’s lab at the University of Pittsburgh School of Medicine, who had helped develop a monkey model that mimicked the characteristics of human TB and devised methods to track and quantify bacterial load and killing in individual granulomas.
“With TB, the immune response is pretty good but not great, and until recently, the field has tackled that problem with very rudimentary tools. This collaboration is bringing the very best tools and the very best minds to bear on a really hard, really important problem that most of the world ignores because it primarily impacts the global poor,” says co-senior author Sarah Fortune, MD, chair of the Department of Immunology and Infectious Diseases at Harvard Chan and an associate member of the Ragon Institute.
The researchers discovered that bacterial persistence occurs in granulomas populated with specific cells, such as mast, endothelial, fibroblast, and plasma cells, which communicate with one another via unique pathways.
Other types of cells, such as type 1-type 17, stem-like, and cytotoxic T cells, are seen in granulomas that facilitate bacterial clearance and use different communication pathways.
“Our findings highlight new targets such as specific cell subsets to guide next-generation vaccines,” says Shalek. “We can also begin to consider how we might directly manipulate entire granulomas through modulating intercellular signaling to combat the bug more effectively.”
TB was the top cause of death from infectious disease until the COVID-19 pandemic, according to Fortune.
“An effective vaccine is the only way that we are really going to control TB, which shares many of the features that has made controlling COVID-19 hard: its airborne transmission, its infection in many people, and its ability to transmit before people are diagnosed,” she says.
Unlike COVID-19, which is caused by a virus, tuberculosis is caused by bacteria, and the current treatment entails months of antibiotic medication.
“This study’s new insights into how the immune system clears, or in some cases helps, TB are critical in figuring out what a new vaccine should do,” says Fortune.
The Bill and Melinda Gates Foundation, Searle Scholars Program, Beckman Young Investigator Program, Sloan Fellowship in Chemistry, National Institutes of Health, American Lung Association, National Science Foundation, Fannie and John Hertz Foundation Fellowship, and Wellcome Trust Fellowship all contributed to this research.
