Tue. May 30th, 2023
enlarge / “Brah, slow down your roll!” From a manuscript by the early medical writer Roger of Salerno (c.1200).

An ancient bacterium known for ravaging and disfiguring its victims has frantically destroyed its own genome to maintain its killer status, according to a new study.

Arran Reeve, suffering from leprosy, circa 1886.
enlarge / Arran Reeve, suffering from leprosy, circa 1886.

tribes from Mycobacterium leprae—the main bacterium behind leprosy* — hypermutates and becomes extremely resistant to drugs. Researchers made the alarming discovery in a study of 154 M. leprae taken from 25 countries. The study, recently published in nature communicationoffers a rare genetic glimpse of the ancient but cryptic bacteria, which still manages to cause 200,000 new cases worldwide every year.

The international team of researchers, led by Stewart Cole of the Ecole Polytechnique Fédérale de Lausanne in Switzerland, noted that the hypermutational state “is likely to promote the emergence of drug resistance.” But there is a catch. Because M. leprae already has a concise genome, it can also be “harmful and ultimately fatal,” he and his team write. In short, the accelerated mutation rate could indiscriminately damage genes essential for survival.

The genetic peek into what? M. leprae handling strains worldwide is a rare opportunity, despite the bacteria’s long history in humans. Leprosy probably originated way back in the Iron Age (1200-600 BC) and has plagued us ever since. In 1873, physician Gerhard Henrik Armauer Hansen was the first to link bacteria to the disease. He reported that when he dropped water on human cells scraped from a leper nodule, “rod-shaped bodies” erupted. Those rod-shaped bodies were… M. leprae, and the sighting marked the first time in history that a bacterium was associated with a chronic disease. Hansen’s discovery gave rise to the other name for leprosy, Hansen’s disease.

Astonishing Plague

Yet more than a century later, relatively little is known about leprosy. The bacterium is extremely difficult to study because of its unique biology: it grows frustratingly slow, lives in cells and broadcasts cryptically. As such, scientists have yet to figure out how to grow M. leprae just in labs, exactly how it causes disease, why it is killed by some antibiotics, and how it travels. It remains a public health threat in South America, Africa, South and Southeast Asia and Micronesia, where it infects approximately 200,000 annually.

When it infects humans, researchers know it usually lodges in peripheral nerve cells. Some evidence suggests: M. leprae reprograms the cells into a “stem cell-like” state to do its bidding. Infection leads to the inflammation, granulomas and systemic bacterial spread within the patient. Ultimately, patients also suffer from sensory loss, disability and distortions. If left untreated, the infection can be fatal.

Until now, researchers still do not know how the bacterium does this or how it ends up in its victims. Direct transmission between humans is considered the most likely case, but some experts have suggested the spread by insects and animals. M. leprae is known to infect mice, armadillos, red squirrels, and some non-human primates.

In the past, the only way researchers could get enough M. leprae for genetic studies was to infect mice and armadillos in the lab — and then wait a year. M. leprae takes 14 days to go through one generation. On the other hand, E coli can do this in 20 minutes. Its slow growth, together with its intracellular residence, allow extracting M. leprae of human tissue incredibly difficult.

But for the new study, Cole and colleagues circumvented the problem. They have worked out and optimized a way to isolate M. leprae from punch biopsies of human tissue. The trick was to disrupt the human cells first, break down the human DNA, then try to tear the bacteria and collect as much bacterial DNA as possible.

Malformed DNA

The team analyzed M. leprae taken from 147 human samples, six red squirrels and one armadillo from around the world (see diagram). All samples were from natural infections. The researchers looked at how the strains related to each other, how they appeared to evolve, and at mutations linked to drug resistance.

From their kinship analysis, the researchers found that the tribes that belonged to the oldest lineage in their collections came from East Asia. This is consistent with previous work suggesting that leprosy originated in Eurasia and spread along human migration routes to Africa and the Americas.

But the researchers noticed eight strains that were hypermutated, which came from five different subtypes of the bacteria. These hypermutants contain large numbers of mutations throughout their genome. They also all had broken versions of a gene that would normally allow the bacteria to read and repair DNA sequence errors, which explains the hypermutation.

The team also noted a stepwise development of antibiotic resistance, particularly in some hypermutants. Since the 1980s, leprosy has been treated with a combination of two to three antibiotics, most commonly rifampicin, dapsone, and clofazimine, although it is unclear how deadly clofazimine is. M. leprae. Doctors sometimes prescribed single antibiotics for this.

For several strains that were resistant to three or more drugs (extended drug-resistant, or XDR strains), the researchers looked back at the medical records of the patients whose strains doctors isolated. The researchers noted that in several cases, the XDR strains infected patients over decades, with resistance to individual drugs developing one by one as new drugs were tried.

“Drug resistance is alarming for the fight against leprosy,” the authors note. And their new study has unearthed entirely new mutations that could make bacteria resistant to drugs in ways never seen before.

“Our discovery of these mutations … should encourage further experimentation to establish their true role and contribution to antimicrobial resistance,” the authors conclude.

*A second leprosy bacterium, Mycobacterium lepromatosis, was discovered in 2008 and has been found infecting red squirrels and humans.

nature communication2018. DOI: 10.1038/s41467-017-02576-z (About DOIs).

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By akfire1

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