Epigenetics May Explain How Tuberculosis Develops Antibiotic Resistance

Tuberculosis (TB) may be one of the oldest and deadliest diseases in history, but it is still very much a threat to people all over the world. Despite the availability of effective treatments and efforts to control it, TB ranks among the top 10 deadliest infectious diseases today. Treatment usually includes a multiple drug course that is given over 6 to 30 months. Not only is this grueling for a patient to endure, but it is also sometimes ineffective due to drug-resistant strains that develop during treatment.

Medical experts have been unable to explain exactly how this disease, which is caused by a species of slow-growing bacteria, develops resistance so quickly. Genetically, the pathogen appears to be static. Yet, it’s capable of adapting to various drugs and diverse host immune responses. To better understand this phenomenon, scientists are looking beyond the genetic aspect of TB and exploring epigenetics for some answers.

In a study published in eLife, San Diego State University (SDSU) researchers have found new evidence that implicates epigenetics involvement in TB’s drug resistance. In particular, they examined DNA methylation as a probable mechanism for the phenotypic variation observed in M. tuberculosis, the bacteria that causes TB.

According to their paper, this bacterium can rapidly diversify, creating multiple subpopulations of itself with distinct characteristics or phenotypes. They call the process ‘intercellular mosaic methylation’, and it allows for resistant strains to persist. Even though antibiotic treatments can kill many types of bacteria, the vast number of mutations being produced in this manner makes it difficult to eliminate all variations.

Author and Professor of Epidemiology and Biostatistics in the School of Public Health at SDSU, Dr. Faramarz Valafar, believes this occurrence explains why CT lung scans taken of individuals considered “cured” show lesions with probable bacterial activity. “We believe this also explains why diagnostic testing in some patients does not predict treatment failure, and why some patients come back months later with the disease reemerging in a far more resistant state,” said Valafar.

Most often, antibiotic resistance is due to genetic alterations. However, M. tuberculosis uses mechanisms in the epigenetic domain to efficiently adapt to any treatment. In another article, we discussed how P. falciparum, a parasite that causes malaria, uses epigenetics to withstand drug treatment. We have another article that explains how pathogens can use epigenetics to change their behavior so that they can coexist within their host.

Pathogens can use an assortment of strategies to manipulate host cells to their benefit. Epigenetic mechanisms such as DNA methylation and chromatin structure are essential in regulating gene expression during cellular response to environmental stimuli. Bacterial infections can profoundly affect the host epigenome, triggering susceptibility to diseases.

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Previous studies have suggested that epigenetics plays a role in bacterial and host factors that contribute to the progression of M. tuberculosis infection. The researchers of this study have been investigating epigenetics in TB for some time. Valafar and first author, Samuel Modlin, began focusing on this subject in 2016. They were then joined by doctoral student Derek Conkle-Gutierrez a few years later at SDSU’s Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence.

Conkle-Gutierrez said, “We’ve known for decades that bacterial epigenetics can influence the expression of certain genes, which can lead to a variety of phenotypes even when they have identical genotypes. We discovered evidence of that phenomenon in the TB bacterium.”

The team collaborated with other researchers around the world to analyze a variety of drug-resistant samples from hundreds of TB patients in China, India, Europe, the Philippines, and South Africa.

They found that some of the samples had mutations that led to variable DNA methylation. “Those strains had much more diversity in their epigenome,” said Modlin, “and thus more potential to be drug-resistant.”

Interestingly, there were no set patterns observed, and methylation was somewhat random. Therefore, the researchers characterized and compared differences among cells within a colony from a single isolate, or individual, using the latest genomic and epigenomic technology – including next-generation sequencing and bioinformatics. Considering that the reference genome did not have a common structure, they recreated each individual genome and evaluated its epigenetic signatures. This allowed them to identify even the slightest of variations that could possibly offset gene expression.

The next step for the team involves further testing to confirm the primary genes identified here with methylation signatures. While more research is needed, it is predicted that their discovery will lead to diagnostic use.

“There is a lot of resistance in TB that escapes current molecular diagnostics, and we don’t really know why.” said Valafar. He believes this study offers a “new domain, new tools, and a new approach” to search for alternative mechanisms. He emphasized that we need to “move away from the classical view of molecular diagnostics and use a novel, comprehensive approach to analyzing bacteria.”

Although current TB treatments effectively prevent and destroy bacteria growth, they do not inhibit intercellular mosaic methylation. Hopefully, targeting this newfound diversification mechanism will prevent short-term epigenetic resistance, killing the bacteria before it mutates in the genome and causes long-term resistance.

TB has been a devastating disease for far too long, and drug resistance has been a leading reason why. Now that we have evidence implicating epigenetics for its persistence, perhaps we use this information to develop treatments and prevention methods that will finally eradicate this highly infectious disease for good.

Source: Modlin S. J. et al. (2020). Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates. eLife, 2020; 9

Reference: Padma Nagappan P (2020). Solving a Mystery: How the TB Bacterium Develops Rapid Resistance to Antibiotics. San Diego State University

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