Tuberculosis is usually encountered as a disease of the lungs, but in 2 percent of cases in the U.S. it can also be found in the bones. The 9,000-year-old skeletons of some Egyptian mummies show signs of having tuberculosis infection in their bones, a painful condition that leaves the bones looking like they’ve been gnawed. 

So it was a weird puzzle when the senior author encountered a Wake County TB outbreak in the mid-2000s in which the infection had spread beyond the lungs in six people. “Four out of six were in the bone,” the author said. “That’s way more than 2 percent.”

The index case, the first person in Raleigh to have this strain of the disease, apparently contracted the bacterium in Vietnam, but he wasn’t feeling very sick and had been working around 400 people in his workplace.

“So it was prolonged exposure in a workplace,” said the author who tracked down and identified seven subsequent infections through contact tracing and health department records.

All eight people were treated with antibiotics and other co-workers received preventative care and then the strange outbreak went away. But the mystery was never really solved. “I’m an epidemiologist and clinical trial specialist and I was left scratching my head,” the author said.

Until several years later when the author had a chance conversation with a colleague “We met up and we're having coffee one day, and we're talking about this,” the author recalls. Academic medical centers routinely keep biological specimens. Their findings appear online Nov. 9 in the journal Cell.

“Certain infections tend to go certain places,” the author said. “And the question is always, why does it do that?” In TB strains found in the Americas and Europe, the bacteria seem more likely to stay put in the lungs. But this strain was highly mobile.

The team ran genetic sequencing on the Raleigh bug and found it most resembled an ancestral strain from a group of strains called lineage 1. In the U.S. we tend to see the modern strains, lineages 2, 3, and 4, but lineage 1 is still out there, mostly in South and Southeast Asia.

Mycobacterium tuberculosis generally infects a type of white blood cell called a macrophage, a highly mobile street sweeper cell that moves around looking for invaders and then engulfs them and chews them up. (Macrophage is Latin for big eater.) One part of the pathogenic bacteria’s toolkit is a set of unique chemical signals – secreted factors -- to protect itself from the immune system and tell its macrophage host what to do.

The team wanted to find the difference that allowed the Wake County bug’s macrophages to be more mobile and leave the lungs.

They compared genetic variants from 225 different strains of TB with particular attention to the genes for their secreted factors. What they found is a secretion factor called EsxM that was active in the Raleigh bacteria, but had been inactivated by a mutation in the modern strains.

Then they looked at genetic sequencing from 3236 different strains of TB and found the pattern persisted: the modern strains have a silenced version of the EsxM secretion factor. “Over a few thousand strains, that really holds up,” the author said. “They’ve maintained that and presumably it’s something that’s evolutionarily advantageous to them.”

To further prove their point, the researchers put active versions of EsxM into safely attenuated versions of modern strains and watched as their macrophage hosts in a lab dish became more active and mobile. “We can see these changes in macrophage shape and structure and they become more migratory,” the author said. They also knocked out EsxM in a strain with the ancestral version and made the infected macrophages less mobile.

While being careful not to overstate their findings, the author said it would appear that the broadly distributed modern strains of TB benefit from staying within the lungs because of the way they spread through the air by breathing. Staying in the lungs would presumably give them a better launching pad to a new host.

Fortunately, the migratory TB strain hasn’t been seen again locally, the author said, “hopefully because we did good work and got a lot of people preventative therapy.” But the mystery of its strange mobility has been solved.

https://www.cell.com/cell/fulltext/S0092-8674(22)01361-7

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fan-ancestral&filter=22