Tuberculosis (TB) is one of the world’s most vexing public health problems. About 1.5 million people died from this bacterial lung infection in 2018, and the World Health Organization (WHO) estimates that one-quarter of the world’s population — some 2 billion people, mostly in developing countries — are infected with the bacteria that causes TB.
For decades, scientists have been studying the deadly disease in mice and other animal models to develop drug therapies and vaccines to treat or prevent the infection. But findings in animals with TB don’t always translate well to people with the disease, leaving scientists puzzled by the discrepancies.
Now, a new study led by Washington University School of Medicine in St. Louis offers a genetic road map detailing the similarities and differences in immune responses to TB across three species — mice, macaques and humans. According to the researchers, the insight into the immune pathways that are activated in diverse models of TB infection will serve as a valuable tool for scientists studying and working to eradicate the disease.
The research, appearing in the journal Science Translational Medicine, is a collaboration between Washington University; the Texas Biomedical Research Institute in San Antonio; and the University of Cape Town in South Africa.
Unlike many previous mouse studies, the new research involved genetically diverse mice that more closely recapitulate the wide range of TB infection severity in humans: Some infected individuals show no symptoms; others show intermediate degrees of severity; and still others develop extreme inflammation of the lungs.
Past research from this long-running clinical trial identified a group of 16 genes whose activation patterns predicted the onset of TB disease more than a year before diagnosis. These genes — called a human TB gene signature — differed significantly in their activation patterns between young people who developed symptoms of TB and those who didn’t.
In macaques, primates closely related to humans, scientists have long assumed that TB infection closely resembles such infection in people.
“Our data demonstrate that 100 percent of the genes previously identified as a human TB gene signature overlap in macaques and people,” said co-senior author Makedonka Mitreva, PhD, a professor of medicine and of genetics at Washington University and a researcher at the university’s McDonnell Genome Institute. “It’s important to have the definitive data showing it to be true.”
There was significant overlap between humans and mice as well, according to the researchers, but they also identified genetic pathways that differed between mice and humans, providing detailed analysis of areas where TB in mice is unlikely to point to meaningful insight into human TB infection.
The researchers studied in detail the genes that increase in expression in people who develop severe TB disease. Of 16 such genes identified in people they were able to study 12 in mice. Four of the genes could not be studied because mice don’t have equivalent versions of such genes or, when such genes were eliminated, the mouse embryos died during development.
The scientists found that the 12 genes fall into three categories: those that provide protection against TB infection; those that lead to greater susceptibility to TB infection; and those that had no effect either way. Such information will be useful in seeking future therapeutics that could, for example, boost effects of protective genes or shut down harmful ones.
The researchers plan to use the new knowledge to better understand TB infections that have become drug-resistant, a growing problem in places where the disease is endemic. In addition, they will harness the information to help understand why the TB vaccine often administered to high-risk groups of people works well in some individuals but not others.