Telomerase helps immune cells fight mycobacteria

Age is a major risk factor for infections such as tuberculosis (TB), and researchers are trying to understand why immune defence weakens over time. One clue comes from telomeres — protective caps on chromosome ends — and the enzyme telomerase that helps maintain them. Telomerase is active in immune cells, but leukocyte telomere length declines with age. Observational studies have linked shorter leukocyte telomeres to worse outcomes in TB patients, but it was unclear how telomere biology actually affects the ability to control mycobacterial infection. To investigate this question in a controlled laboratory setting, Stefan H. Oehlers and colleagues turned to the zebrafish-Mycobacterium marinum model, a well-established system for studying TB-like disease. They focused on Tert, the catalytic subunit of telomerase, to ask whether reducing telomerase function changes how well an organism can resist mycobacterial infection. By manipulating Tert in the zebrafish model, the team aimed to link molecular telomerase activity with immune-cell behaviour and infection outcomes, providing a clearer mechanistic picture than observational human studies alone can offer.

Using the zebrafish-Mycobacterium marinum infection model, the researchers depleted and inhibited Tert and then monitored infection outcomes in zebrafish embryos. They found that reducing Tert increased bacterial burden, showing that telomerase activity directly influences the capacity to control mycobacterial growth. To explore possible pathways behind this effect, the team tested whether removing other immune regulators could reverse the increased susceptibility: neither p53 nor STING depletion rescued the Tert depletion phenotype. This negative result indicates the effect is not mediated by those canonical immune-stress or innate-sensing pathways and points to a different, non-canonical role for Tert. Consistent with prior descriptions of Tert’s role in developmental hematopoiesis, the study showed that Tert is required for demand-driven emergency myelopoiesis — the rapid production of myeloid immune cells during sustained infection — which helps contain extended mycobacterial infection. Taken together, these methods and results establish that host telomerase, via Tert, supports the production of immune cells needed during prolonged infection and thereby affects bacterial control.

These findings identify a previously undescribed role for telomerase in infection control: rather than acting only to preserve chromosome ends, Tert supports the immune system’s ability to ramp up myeloid cell production when infections persist. That role helps explain why shorter leukocyte telomeres and presumed loss of telomerase activity in ageing immune systems might contribute to worse TB outcomes. Because the work used the zebrafish-Mycobacterium marinum model, the study provides a mechanistic link that complements human correlations between leukocyte telomere length and TB severity, though further work will be needed to translate the findings to humans. The discovery opens new directions for research into how maintaining telomerase activity in immune cells could affect resistance to mycobacterial disease and suggests that measures of telomere biology might inform risk assessment or the development of therapies aimed at supporting infection-driven hematopoiesis during prolonged infections.