HflX controls hypoxia-induced non-replicating persistence in slow growing mycobacteria
NGAN, J. Y. G.; PASUNOOTI, S.; TSE, W.; MENG, W.; NGAN, S. F. C.; NG, S. W.; JAAFAR, M. T.; JIA, H.; CHO, S. L. S.; LIM, J.; KOH, H. Q. V.; ABDULGHANI, N.; PETHE, K.; Sze, K. S.; Lescar, J.; Alonso, S.
Show abstract
GTPase HflX is highly conserved in prokaryotes and is a ribosome splitting factor during heat shock in E. coli. Here we report that HflX produced by slow growing M. tuberculosis and M. bovis BCG is a GTPase that plays a critical role in the pathogens transition to a non-replicating, drug-tolerant state in response to hypoxia. Indeed, HflX-deficient M. bovis BCG (KO) replicated markedly faster in the microaerophilic phase of a hypoxia model, that precipitated entry into dormancy. The KO displayed the hallmarks of dormant mycobacteria including phenotypic drug resistance, altered morphology, low intracellular ATP and up-regulated dormancy dos regulon. KO-infected mice displayed increased bacterial burden during the chronic phase of infection, consistent with the higher replication rate observed in vitro in microaerophilic phase. Unlike fast-growing mycobacteria, BCG HlfX was not involved in antibiotic resistance under normoxia. Proteomics, pull-down and ribo-sequencing supported that mycobacterial HflX is a ribosome binding protein that controls the translational activity of the cell. Collectively, our study provides further insights into the mechanisms deployed by mycobacteria to adapt to their hypoxic microenvironment.
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