Sequencing studies show how TB moved with humans, adapted to treatments

Mycobacterium tuberculosis is an obligate human pathogen that must cause disease in order to be transmitted. Furthermore, its evolution is tied up with that of people since only humans transmit it, the University of Wisconsin's Caitlin Pepperell said at the ASM Microbe 2018 meeting here.

By sequencing bacterial isolates, she and her colleagues traced its migration across the globe, but they also considered what was occurring within human society at the time.

"What I wanted to do was to embed the genomic data into a sensible historical context," Pepperell said during a session devoted to paleomicrobiology.

She and her colleagues sequenced the whole genomes of 552 M. tuberculosis isolates, which they used to develop a phylogenetic tree. They used evolutionary rate estimates based on ancient DNA calibrations and timed the migration of M. tuberculosis, comparing it to human movements during that era, as they also reported in a preprint in BioRxiv.

The timing of the mass dispersal of M. tuberculosis coincided with a time of increased trade among humans, Pepperell said. The bacterium, she added, appeared to be moving along human trade routes such as the Silk Road.

While increased human interconnectedness and disease spread is typically thought of as a modern problem, Pepperell noted increased global travel also contributed to bacterial movements back then. She further pointed out that M. tuberculosis spread was efficient and followed complex patterns. She noted there were exchanges between bacteria in eastern Africa and in Southeast Asia. "The bacteria was zipping around the Indian Ocean, no big deal," she said.

Pepperell added, though, that China and East Asia did not appear to contribute to this historical spread of tuberculosis, which she noted was surprising as there is a large M. tuberculosis population there now.

She teamed up with researchers at Fudan University who were also studying M. tuberculosis. They analyzed 4,578 M. tuberculosis isolates from all Chinese provinces to find that there were likely four events that introduced tuberculosis to China. They further uncovered remarkably low genetic diversity — Pepperell said that the countrywide genetic diversity of M. tuberculosis in China was lower than that of cities in India.

When they then viewed their result through a historical lens, Pepperell said that China's isolationist policies at that time might have prevented additional introductions of M. tuberculosis.

Pepperell also noted that tuberculosis evolves clonally, with not a lot of horizontal gene transfer, which is typically important for antibiotic resistance. She and her colleagues examined the whole genomes of more than 1,000 M. tuberculosis isolates and particularly homed in on known drug-resistance loci to tease out a genomic signature.

These loci, Pepperell said, were either "tight" or "sloppy." Tight targets had just a few mutations crop up again and again, while sloppy targets harbored a wider range of mutations. One tight target, KatG, had one isoniazid resistance mutation affecting the serine at position 315 emerge repeatedly as she and her colleagues also reported in an mSystems paper published earlier this year. This mutation, Pepperell said, must have had the lowest cost to other aspects of fitness.

By contrast, the sloppy target pncA harbored 62 nonsynonymous mutations in their dataset, they reported.

She and her colleagues also examined human cultural adaptations to tuberculosis and its treatment. Sanatoriums for tuberculosis patients open in the 1830s, isolating them from the public. They hypothesized that with the advent of anti-tuberculosis drugs, that patients' stay there would be shortened. However, by sifting through admissions data, they found that the length of admission increased to more than 14 months and that the number of repeat and overall admissions also increased.

Source: GenomeWeb