| Autor: |
Grace Ngan, Jie Yin, Pasunooti, Swathi, Tse, Wilford, Wei Meng, So Fong Cam Ngan, Huan Jia, Jian Qing Lin, Sze Wai Ng, Jaafa, Muhammad Taufiq, Su Lei Sharol Cho, Jieling Lim, Hui Qi Vanessa, Koh, Ghani, Noradibah Abdul, Pethe, Kevin, Siu Kwan Sze, Lescar, Julien, Alonso, Sylvie |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 3/23/2021, Vol. 118 Issue 12, p1-10, 10p |
| Abstrakt: |
GTPase high frequency of lysogenization X (HflX) is highly conserved in prokaryotes and acts as a ribosome-splitting factor as part of the heat shock response in Escherichia coli. Here we report that HflX produced by slow-growing Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a GTPase that plays a critical role in the pathogen's transition to a nonreplicating, 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 resulted in premature entry into dormancy. The KO mutant displayed hallmarks of nonreplicating mycobacteria, including phenotypic drug resistance, altered morphology, low intracellular ATP levels, and overexpression of Dormancy (Dos) regulon proteins. Mice nasally infected with HflX KO mutant displayed increased bacterial burden in the lungs, spleen, and lymph nodes during the chronic phase of infection, consistent with the higher replication rate observed in vitro in microaerophilic conditions. Unlike fast growing mycobacteria, M. bovis BCG HlfX was not involved in antibiotic resistance under aerobic growth. Proteomics, pulldown, and ribo-sequencing approaches supported that mycobacterial HflX is a ribosome-binding protein that controls translational activity of the cell. With HflX fully conserved between M. bovis BCG and M. tuberculosis, our work provides further insights into the molecular mechanisms deployed by pathogenic mycobacteria to adapt to their hypoxic microenvironment. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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