Combination of two antibiotics eradicates latent tuberculosis in macaques
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% 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, including co-first authors Mushtaq Ahmed, PhD, an assistant professor of molecular microbiology in Khader's lab; Shyamala Thirunavukkarasu, PhD, a staff scientist in Khader's lab; and Bruce A. Rosa, PhD, an assistant professor of medicine in Mitreva's lab. 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.
"Until now, we have studied mouse models to understand TB disease progression, not knowing where the mouse disease translates to human disease and where it doesn't," Khader said. "Now, we have shown that many areas do translate but that there are important aspects of TB infection that don't. If you are using mouse models to develop TB vaccines or other therapeutics that target areas that don't overlap, you likely won't succeed."
Added Mitreva, "Our study will inform researchers when they may need to move to a different animal model to study their genetic or molecular pathways of interest."
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.
According to Khader and Mitreva, their team plans 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.
With the study's raw data publicly available, Khader and Mitreva said they are hopeful it will serve as a valuable resource to TB research and immunology communities worldwide. Source:
Washington University School of Medicine Journal reference:
Ahmed, M., et al . (2020) Immune correlates of tuberculosis disease and risk translate across species. Science Translational Medicine . doi.org/10.1126/scitranslmed.aay0233 .
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