Tuberculosis that "eats bones"

Tuberculosis is usually a lung disease, but it can also be found
in bones in 2% of cases in the United States.
The bones of some 9,000-year-old Egyptian mummies show signs of tuberculosis, a painful condition that makes the bones look like
they've been gnawed.

So it was a strange puzzle when Duke physician Jason Stout encountered a tuberculosis outbreak in Wake County in the mid-2000s, when the infection spread beyond
the lungs in 6 people.
"Four sixths are in the bones," Stout said
.
"That's much more than 2 percent
.
"

The index case was the first person in the city of Raleigh to contract this strain, he apparently contracted the bacterium in Vietnam, but he did not feel very uncomfortable and has been dealing with
more than 400 people at his workplace.

Stout, a professor of medicine at Duke University, said: "So it's the result of prolonged exposure in the
workplace.
" He traced and confirmed 7 subsequent infections
through contact tracing and health department records.

All 8 people were treated with antibiotics, other colleagues also received preventive care, and then the strange outbreak disappeared
.
But the mystery was never really solved
.
"I'm an epidemiologist and clinical trial specialist, and that leaves me scratching my head
," Stout said.

It wasn't until a few years later that Stout had a chance conversation with his colleague and TB researcher Dr.
David Tobin, an associate professor
of molecular genetics, microbiology and immunology at Duke University.

"We met, we had coffee together one day, and we talked about it," Stout recalls
.
Academic medical centers such as Duke regularly preserve biological specimens, and Stout still has samples
of this puzzling strain.
"David said, 'Okay, give it to me and we'll see
.
' And then this amazing science came from that," Stout said
.

The amazing science is that Tobin's lab and several colleagues at Duke, Notre Dame, and the University of Texas figured out exactly how and why these particular TB bacteria flowed the way they did
.
Their findings were published Nov.
9 in the journal Cell
.

"Certain infections tend to reach certain places
," Tobin said.
The question is, always, why does it do this?" In strains of tuberculosis found in the Americas and Europe, the bacteria appear to be more likely to lodge in the lungs
.
But this strain is highly fluid
.

They genetically sequenced this Raleigh case and found that it most resembled one of the ancestor strains in a group of strains
called "lineage 1.
" In the United States, we tend to see modern strains, lineages 2, 3, and 4, but lineage 1 still exists, mainly in South and Southeast Asia
.

Mycobacterium tuberculosis usually infects a type of white blood cell called macrophage, a highly fluid street-sweeping cell that moves around looking for invaders and then devours and chews them
.
Macrophage means "big eater" in Latin
.
Part of the pathogenic toolbox is a unique set of chemical signals — secreted factors — to protect themselves from the immune system and tell the macrophage host what to do
.

Tobin's team wanted to find the difference
where macrophages move more easily and leave the lungs.

They compared the genetic variation of 225 different strains of TB, paying particular attention to the genes
of their secreted factors.
What they found was a secreted factor called EsxM, which was active in Raleigh but was inactivated by a mutation in modern strains
.

Then, in collaboration with Craig Lowe, an evolutionary biologist and assistant professor of molecular genetics and microbiology at Duke University, they genetically sequenced 3236 different TB strains and found that the pattern persisted: Modern strains have a silent EsxM secretion factor
.
Tobin said: "In a few thousand strains, this does hold
.
It has always insisted on this, presumably as something
good for their evolution.
”

To further prove their point, the researchers put the active version of EsxM into a safe attenuated version of the modern strain and observed that they became more active and mobile
in the macrophage host in a lab dish.
"We can see changes in the shape and structure of macrophages, they become more migratogenous
," Tobin said.
They also knocked out EsxM from the strain with the original version and reduced the ability of infected macrophages to move
.

While Tobin was careful not to exaggerate their findings, he said that because of the way they travel through the air by breathing, widespread modern TB strains appear to benefit from staying in the lungs
.
Staying in the lungs may give them a better launch pad to find new hosts
.

Fortunately, migrating TB strains did not reappear locally, Stout said, "and hopefully because we did a good job getting a lot of people to get preventive treatment
.
" But its peculiar liquidity mystery has been solved
.

"It's likely to start with me saying, 'Wow, this is
weird.
There must be something wrong with the strain because all these patients have healthy immune systems,'" Stout said
.
"But the science I do is different
from the science that David does.
This is a great example of people from different disciplines coming together to answer a really interesting clinical question
.
”