Tuberculosis (TB) is usually found in the lungs, but there's an ancient lineage of TB that specializes in spreading to the bones and damaging them from the inside, researchers have discovered.
However, something strange happened during a TB outbreak in the mid-2000s in North Carolina. At the epicenter of this outbreak was a person who had apparently caught TB in Vietnam.
The disease was passed on in a workplace setting. Of the six people whose TB infections had spread beyond the lungs, four had reached the bone.
"That's way more than two percent," says infectious disease physician Jason Stout from Duke University.
The chances of this happening randomly were astronomical (approximately 5×10-6).
This scientific puzzle kept niggling away in the back of Stout's mind for several years, until a chance encounter with Duke University molecular geneticist David Tobin revealed an opportunity.
Tobin offered to examine some samples taken from the people who were infected during this unusual TB outbreak.
We know that the bacteria that causes TB (Mycobacterium tuberculosis) moves around the body by invading macrophages – immune cells that swallow pathogens. Stout and Tobin wanted to find out what makes some types of TB more mobile inside the human body than other types of TB.
In a paper published in Cell, the researchers compare the genetic sequence of the TB strain responsible for the North Carolina outbreak with 225 other strains of TB.
They found that the outbreak was caused by a lineage 1 strain, which was one of the earliest forms of TB to emerge.
Today, the lineage 1 strain is responsible for a large burden of disease, but is geographically restricted to countries that border the Indian Ocean.
Specifically, the researchers found that a particular gene that codes for a protein – the EsxM variant – was present in full in the North Carolina TB outbreak strain, but truncated in the 'modern' TB strains (Lineage 2, 3, and 4).
A previous study from the UK of over 1,600 people suggested that lineage 1 TB was associated with higher rates of skeletal TB than the 'modern' lineages.
To confirm that the full-length EsxM variant was necessary and sufficient to cause TB-infected macrophages to travel further, the researchers infected zebrafish with the North Carolina TB outbreak strain and examined how far the macrophages traveled.
They then infected a separate group of zebrafish with a TB strain that contained a mutant EsxM variant. The travel distance of macrophages infected with a mutant TB strain was two-fold shorter than those with the full-length EsxM variant.
The researchers also showed that macrophages with the mobility gene were much faster at moving to the site of a tail fin wound than macrophages without this gene.
The researchers also sequenced 3,236 different strains and found all the modern ones have the silenced EsxM gene. This suggests the mutation has a strong evolutionary advantage.
The team suspects that while the mutation restricts TB within the body, it has also allowed 'modern' TB strains to spread more widely by staying put in the lungs, giving it more concentrated air dispersal abilities via an infected patient's breathing.
This paper was published in Cell.