Han, D. J.; Costa, D. M.; Luo, G.; Wright, K.; Pandey, M.; Wee, D.; Chen, Y.; Akincilar, S. C.; Tergaonkar, V.; Dorajoo, R.; Carissimo, G.; Singhal, A.; Elks, P. M.; Ellis, P. S.; Henriques, C. M.; Yan, B.; Mostowy, S.; Oehlers, S. H.

Age is an important risk factor for infections such as tuberculosis (TB). Telomerase is expressed in immune cells yet leukocyte telomere length declines during ageing suggesting an age-dependent loss of telomerase activity in the immune system. Leukocyte telomere length has been correlated with worse outcomes in TB patients, however the mechanisms linking telomere biology to TB susceptibility and response to therapy are unexplored. Here we use the zebrafish-Mycobacterium marinum model to investigate the role of telomerase in TB resistance. We find depletion and inhibition of Tert, the catalytic subunit of telomerase, increases bacterial burden in zebrafish embryos while small molecule activation of Tert decreases bacterial burden. Depletion of shelterin components did not recapitulate the infection susceptibility phenotype, and infection susceptibility could not be rescued by p53 or STING depletion. Consistent with a previously described role for Tert in developmental hematopoiesis, we find Tert is necessary for demand-driven emergency myelopoiesis to support containment of extended mycobacterial infection. Our findings establish a previously undescribed role for host telomerase in supporting infection demand-driven hematopoiesis to control infection.