Mycobacterium tuberculosis arrests host cycle at the G1/S transition to establish long term infection

PLoS Pathogens

Adrie J. C. Steyn¹  John H. Adamson¹  Bridgette M. Cumming¹  Md. Aejazur Rahman¹  Dirk A. Lamprecht¹  Kyle H. Rohde²  David G. Russell³  Vikram Saini⁴ 

[1] Africa Health Research Institute, Durban, KwaZulu Natal, South Africa;Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America;Cornell University College of Veterinary Medicine, C5 171 Veterinary Medical Center, Ithaca, New York, United States of America;Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America

关键词: Mycobacterium tuberculosis;    Macrophages;    Cell cycle;    cell division;    Host cells;    Lipids;    Bioenergetics;    Respiratory infections;    Homeostasis;   

DOI  :  10.1371/journal.ppat.1006389

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Signals modulating the production of Mycobacterium tuberculosis (Mtb) virulence factors essential for establishing long-term persistent infection are unknown. The WhiB3 redox regulator is known to regulate the production of Mtb virulence factors, however the mechanisms of this modulation are unknown. To advance our understanding of the mechanisms involved in WhiB3 regulation, we performed Mtb in vitro, intraphagosomal and infected host expression analyses. Our Mtb expression analyses in conjunction with extracellular flux analyses demonstrated that WhiB3 maintains bioenergetic homeostasis in response to available carbon sources found in vivo to establish Mtb infection. Our infected host expression analysis indicated that WhiB3 is involved in regulation of the host cell cycle. Detailed cell-cycle analysis revealed that Mtb infection inhibited the macrophage G1/S transition, and polyketides under WhiB3 control arrested the macrophages in the G0-G1 phase. Notably, infection with the Mtb whiB3 mutant or polyketide mutants had little effect on the macrophage cell cycle and emulated the uninfected cells. This suggests that polyketides regulated by Mtb WhiB3 are responsible for the cell cycle arrest observed in macrophages infected with the wild type Mtb. Thus, our findings demonstrate that Mtb WhiB3 maintains bioenergetic homeostasis to produce polyketide and lipid cyclomodulins that target the host cell cycle. This is a new mechanism whereby Mtb modulates the immune system by altering the host cell cycle to promote long-term persistence. This new knowledge could serve as the foundation for new host-directed therapeutic discovery efforts that target the host cell cycle.

【 授权许可】

CC BY