TB strain infectivity is linked to shared geographic background

For some forms of tuberculosis, the chances that an exposed person will become infected depend on whether the individual and the bacteria share a hometown, according to a new study comparing how different strains move through mixed populations in cosmopolitan cities.

Results of the research, led by Harvard Medical School scientists and published in Nature Microbiology, provide the first hard evidence of long-standing observations that have led scientists to suspect that pathogen, place, and human host collide in a distinctive interplay that influences infection risk and fuels differences in susceptibility to infection.

The study strengthens the case for a long-standing hypothesis in the field that specific bacteria and their human hosts likely co-evolved over hundreds or thousands of years, the researchers said.

The findings may also help inform new prevention and treatment approaches for tuberculosis, a wily pathogen that sickens more than 10 million people and causes more than a million deaths worldwide each year, according to the World Health Organization.

In the current analysis, believed to be the first controlled comparison of TB strains' infectivity in populations of mixed geographic origins, the researchers custom built a study cohort by combining case files from patients with TB in New York City, Amsterdam, and Hamburg. Doing so gave them enough data to power their models.

The analysis showed that close household contacts of people diagnosed with a strain of TB from a geographically restricted lineage had a 14% lower rate of infection and a 45% lower rate of developing active TB disease compared with those exposed to a strain belonging to a widespread lineage.

The study also showed that strains with narrow geographic ranges are much more likely to infect people with roots in the bacteria's native geographic region than people from outside the region.

The researchers found that the odds of infection dropped by 38% when a contact is exposed to a restricted pathogen from a geographic region that doesn't match the person's background, compared with when a person is exposed to a geographically restricted microbe from a region that does match their home country. This was true for people who had lived in the region themselves and for people whose two parents could each trace their heritage to the region.

This pathogen-host affinity points to a shared evolution between humans and microbes with certain biological features rendering both more compatible and fueling the risk for infection, the researchers said.

The new study showed that for geographically restricted strains, whether a person has ancestors who lived where the strain is common was an even bigger predictor of infection risk than bacterial load in the sputum. In the cases analyzed in the study, this risk of common ancestry even outweighed the risk stemming from having diabetes and other chronic diseases previously shown to render people more susceptible to infection.

The findings add to a growing body of evidence of the importance of paying attention to the wide variation between different lineages of tuberculosis and to the details of how different lineages of tuberculosis interact with different host populations.

Previous studies have shown that some genetic groups of TB are more prone to developing drug resistance and that TB vaccines appear to work better in some places than others. There is also evidence that some treatment regimens might be better suited to some strains of TB than others.

These findings emphasize how important it is to understand what makes different strains of TB behave so differently from one another, and why some strains have such a close affinity for specific, related groups of people.

In addition to the analysis of clinical, genomic, and public health data, the researchers also tested the ability of different strains of TB to infect human macrophages, a type of immune cell that TB hijacks to cause infection and disease. The researchers grew cells from donors from different regions. Once again, cell lines from people with ancestry that matched the native habitat of a restricted strain of tuberculosis bacteria were more susceptible to the germs than cells from people from outside the area, mirroring the results of their epidemiologic study.

Differential rates of Mycobacterium tuberculosis transmission associate with host–pathogen sympatry, Nature Microbiology (2024). DOI: 10.1038/s41564-024-01758-y