There are almost 1.8 billion people with tuberculosis bacilli in their body, but only about 5% to 15% develop overt infection, usually within 18 months of initial exposure. The reason behind this selective progression has been sought for decades by scientists from a variety of fields. Now, researchers say they’ve found at least part of the answer: differences in the genetic make-up play a key role, and at least one of them works by the effect it has on immune function.
The progression of latent tuberculosis to active infection may occur in one of two ways: early progression which occurs within months, and late-onset progression which takes years or even decades, and is more easily traced to weakened immunity and/or aging-related vulnerability. In the former case, people with weaker immune defenses who fail to stop the infection in its tracks are more likely to progress to overt infection.
3D illustration of bacterium Mycobacterium tuberculosis. Image Credit: Kateryna Kon / Shutterstock
How was the study done?
The study examined people with tuberculosis in Lima, a large Peruvian city, to find the exact gene locus that is associated with loss of immune control and early progression in tuberculosis. They used data on whole-genome analysis of Peruvians from a public database, looking especially for single-nucleotide polymorphisms, or SNPs. These are small regions of the DNA strand that is different from the ‘normal’ sequence by just one nucleotide, which represents one letter in the genetic code. Such minute alterations can change gene function and regulatory function as well. The researchers in this study looked only for SNPs that could be found in Peruvians alone by using specially customized tests.
Then they looked at DNA samples from over 2,000 people with active tuberculosis, and 2,000 people who lived with them and had latent tuberculosis infection. The presence of latent infection in apparently healthy non-progressors was confirmed by standard skin tests, blood tests and X-rays of the chest at baseline, 2, 6 and 12 months.
The study is a pioneering effort to explore genetic links with the activation of tuberculosis infection on a large scale. It looked at people living in the same household settings, some of whom had active and some latent tuberculosis. This study design helped them to compare people with infection who progressed with those who didn’t despite the same environment and exposure pattern, in a direct and relevant manner.
What does the study show?
The study showed that genes that drive a quick and adequate immune response prevent the development of active tuberculosis in most cases. It also shows basic genetic differences in early vs late-onset tuberculosis on the basis of the genes activated in both forms. Researcher Megan Murray says, “Our results indicate that early TB progression is a highly heritable trait and one that is genetically distinct from TB reactivation after years of dormancy.”
Specifically, they found a region on chromosome 3 (chromosome 3q23) that coded for a protein called ATP1B3, which regulates the function of monocytes, an important category of immune cells. These cells are crucial in the first nonspecific counterattack against microbes, called innate immunity, by detecting invaders and mopping up infected or injured cells. This gene locus was altered in early progressors compared to non-progressors.
The reason could be that the gene variant prevents proper monocyte function by disrupting the regulatory process. As a result, the monocyte may simply not be carrying out its normal functions, allowing the tuberculosis bacilli to cause active infection.
Other areas of the genome that may be associated with early progression include some regions associated with the human leukocyte antigen complex that codes for proteins which are responsible for immune recognition of self-antigens (belonging to the same host) in contrast to foreign cells and particles.
The researchers point out that this early finding is likely to drive the discovery of many more genes that cause early disease progression. Researcher Yang Luo says, “The risk regions that we identified may play a vital role in the immune responses for TB progression, but they may not be the end of the story.” Colleague Soumya Raychaudhuri confirms, “There may be lots of other alleles with weaker effects spread around the genome.”
What do we learn?
Many genes affecting tuberculosis progression will probably be found in widely dispersed parts of the genome, though their effects may not be as clear-cut as with ATP1B3. Thus tuberculosis is likely to be a multifactorial disorder, just like cardiovascular disease, which occurs in people who are at risk not only because of various gene mutations but also because of environmental and lifestyle factors.
Knowing which genes cause an increased risk of early progression could boost the development of tests to help screen patients who are at risk, as well as of vaccines or drugs directed specifically against this factor. Raychaudhuri says, “We believe our analysis is the first step on a long journey toward identifying new ways to intervene at these distinct stages and developing strategies that either optimize host immunity or interfere with the pathogen's fitness.”
The study was published in the journal Nature Communications on August 21, 2019.
Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians. Yang Luo, Sara Suliman, Samira Asgari, Tiffany Amariuta, Yuriy Baglaenko, Marta Martínez-Bonet, Kazuyoshi Ishigaki, Maria Gutierrez-Arcelus, Roger Calderon, Leonid Lecca, Segundo R. León, Judith Jimenez, Rosa Yataco, Carmen Contreras, Jerome T. Galea, Mercedes Becerra, Sergey Nejentsev, Peter A. Nigrovic, D. Branch Moody, Megan B. Murray & Soumya Raychaudhuri. Nature Communications, volume 10, Article number: 3765 (2019). https://doi.org/10.1038/s41467-019-11664-1. https://www.nature.com/articles/s41467-019-11664-1#article-info