Immune status reshapes tuberculosis mutations in primates

Tuberculosis is caused by Mycobacterium tuberculosis (Mtb), and researchers are increasingly interested in how the bacteria evolve inside a single infected person or animal. That evolution can influence how infections progress and how well treatments work, but the picture of Mtb change inside hosts — especially when the immune system is compromised by human immunodeficiency virus (HIV) or modified by antiretroviral therapy (ART) — is incomplete. To fill that gap, a team led by Michael C. Chao studied Mtb populations across many infected samples from non-human primates (NHP). They used whole genome sequencing to examine bacteria collected from roughly 480 infected tissues taken from 20 animals. The group included animals that were co-infected with simian immunodeficiency virus (SIV) and animals in which SIV was suppressed or not suppressed by ART. By looking across this large set of samples, the scientists aimed to describe which mutations appear during infection, how those mutations spread between tissues as bacteria disseminate, and whether immune status and ART change the kinds of genetic damage Mtb accumulates during early infection.

The study applied whole genome sequencing to Mtb populations sampled from about 480 infected tissues across 20 non-human primates, including animals co-infected with simian immunodeficiency virus (SIV) with or without virological suppression by ART. From those data the researchers identified 116 mutations that emerged over the course of infection. Some mutations appeared primarily within individual tissues, indicating local overrepresentation, while a subset was shared across tissues, consistent with bacterial dissemination events. Comparing treatment groups revealed distinct mutational trajectories: SIV-infected hosts showed higher mutation rates and greater bacterial outgrowth, whereas coinfected animals on ART had an increased prevalence of oxidative damage-associated mutations. Across animals, the team observed a common pattern of mutation in Mtb lipid metabolism and polyketide synthase genes. Notably, a subset of the mutations detected in these NHP-derived Mtb populations have also independently arisen in human clinical isolates, linking the primate findings to patterns seen in human TB strains.

These results suggest that the immune environment — whether altered by SIV infection or modified by ART — changes both how fast Mtb accumulates mutations and what kinds of DNA damage it sustains. The finding that mutations cluster in lipid metabolism and polyketide synthase genes points to consistent bacterial pathways that respond to host pressures, which could represent routes by which Mtb adapts within a host. That some NHP-derived mutations also appear in human clinical isolates strengthens the relevance of the primate model to human disease and hints that similar selective forces act in people. Importantly, the study shows that ART does not simply return conditions to a pre-infection state: coinfected animals on ART exhibited distinct oxidative damage-associated mutations, implying that treatment changes the immune pressures Mtb confronts. Overall, this population-level sequencing approach captures early diversification, tracks dissemination events, and infers how differing immune states sculpt Mtb evolution during infection.