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Sequencing Study Finds Mutations in Latent Tuberculosis Bugs

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – An online study in Nature Genetics yesterday hints that drug resistance may arise in tuberculosis-causing bacteria even during latent stages of infection.

A Harvard University-led team sequenced the genomes of nearly three-dozen Mycobacterium tuberculosis isolates collected from nine infected macaques. When they used SNP data to gauge mutation rates at different stages of infection, the researchers found comparable levels of mutation under each of the conditions tested. The findings suggest drug resistance — including resistance to a treatment that relies on the antibiotic isoniazid alone — can likely occur even when tuberculosis infection is not at an active stage.

"We show that [M. tuberculosis] continues to acquire mutations during disease latency," senior author Sarah Fortune, an immunology and infectious diseases researcher with the Harvard School of Public Health, and her co-authors wrote, "which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance."

Active tuberculosis is typically tackled with a combination of different antibiotics, the researchers explained. Latent infections, on the other hand, are considered less mutation prone, and are more often treated with a lone antibiotic called isoniazid, or INH.

Nevertheless, some epidemiological studies have reported elevated INH resistance in tuberculosis-causing bugs that had been treated with this preventative monotherapy, the authors explained, raising suspicions that mutations may be more common during latency than previously appreciated — a possibility that the team explored with whole-genome sequencing.

"[W]e sought to define the mutational capacity of the bacterium during infection to better predict the rate at which drug resistance can be expected to emerge in active, latent, and reactivated disease," they wrote.

Using the Illumina Genome Analyzer, the researchers did single-read and paired-end sequencing of a M. tuberculosis strain known as Erdman and of 33 M. tuberculosis isolates from nine macaques that either had active tuberculosis infections, latent infections, or infections that were re-activated after a period of latency.

In the process, they generated sequence that covered 93 percent of each genome, on average, to a depth of about 117 times.

After tracking down variants in the genomes and verifying them with targeted Sanger sequencing, the team was left with 14 SNPs that seem to have arisen over the course of macaque infections. But rather than seeing more mutations in the isolates from macaques with active tuberculosis infections, the researchers found comparable mutation rates in each of the three infection scenarios.

"Our data indicate that in macaques with active, latent, and reactivated disease, the bacterial populations acquire mutations at the same rate over time, regardless of the number of bacterial replications that have occurred," they wrote.

Moreover, their subsequent experiments hint that these mutation rates are similar to those found when M. tuberculosis is grown in a lab setting.

The findings suggest that drug resistance is not only an issue to contend with during active tuberculosis infection, the researchers explained, since bacteria can also mutate during latent infection and in early stages of reactivation.

Those involved in the study emphasize that more research is needed to understand whether M. tuberculosis mutation patterns are similar in infected humans. Still, they say, the results underscore the need for surveillance for resistance-related mutations — particularly if preventative INH treatment becomes more broadly used to treat latent tuberculosis in some populations, including those infected with HIV.

"[INH preventative monotherapy] is now being recommended globally for HIV-positive individuals with latent tuberculosis where bacterial burden and the rate of treatment failure may be higher because of immunocompromise," the authors noted.

"If our data from the macaque model are predictive of the mutational capacity of [M. tuberculosis] in HIV-positive individuals, INH mono-resistance could arise at a substantial rate," they added. "These findings emphasize the importance of drug resistance testing and careful monitoring for treatment in these populations."

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