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About the Authors:
Bridgette M. Cumming
¶‡ Co-first authors
Affiliation: Africa Health Research Institute, Durban, KwaZulu Natal, South Africa
Md. Aejazur Rahman
¶‡ Co-first authors
Affiliation: Africa Health Research Institute, Durban, KwaZulu Natal, South Africa
Dirk A. Lamprecht
Affiliation: Africa Health Research Institute, Durban, KwaZulu Natal, South Africa
ORCID http://orcid.org/0000-0003-1066-9026
Kyle H. Rohde
Affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America
ORCID http://orcid.org/0000-0001-9838-3238
Vikram Saini
Affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
ORCID http://orcid.org/0000-0002-0258-2871
John H. Adamson
Affiliation: Africa Health Research Institute, Durban, KwaZulu Natal, South Africa
ORCID http://orcid.org/0000-0001-7651-2238
David G. Russell
Affiliation: Cornell University College of Veterinary Medicine, C5 171 Veterinary Medical Center, Ithaca, New York, United States of America
ORCID http://orcid.org/0000-0002-9748-750X
Adrie J. C. Steyn
* E-mail: [email protected]
Affiliations Africa Health Research Institute, Durban, KwaZulu Natal, South Africa, Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America, Centers for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America, School of Laboratory Medicine and Medical Sciences, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
ORCID http://orcid.org/0000-0001-9177-8827Abstract
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...