title: Mycobacterial WhiB6 Differentially Regulates ESX-1 and the Dos Regulon to Modulate Granuloma Formation and Virulence in Zebrafish.
abstract: During the course of infection, Mycobacterium tuberculosis (Mtb) is exposed to diverse redox stresses that trigger metabolic and physiological changes. How these stressors are sensed and relayed to the Mtb transcriptional apparatus remains unclear. Here, we provide evidence that WhiB6 differentially regulates the ESX-1 and DosR regulons through its Fe-S cluster. When challenged with NO, WhiB6 continually activates expression of the DosR regulons but regulates ESX-1 expression through initial activation followed by gradual inhibition. Comparative transcriptomic analysis of the holo- and reduced apo-WhiB6 complemented strains confirms these results and also reveals that WhiB6 controls aerobic and anaerobic metabolism, cell division, and virulence. Using the Mycobacterium marinum zebrafish infection model, we find that holo- and apo-WhiB6 modulate levels of mycobacterial infection, granuloma formation, and dissemination. These findings provide fresh insight into the role of WhiB6 in mycobacterial infection, dissemination, and disease development.
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 10086, China.
authors.forename: Zhenkang
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Hu
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa.
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Cumming
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Lu
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Feng
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Jiaoyu
authors.initials: J
authors.lastname: Deng
authors.affiliation: KwaZulu-Natal Research Institute for Tuberculosis and HIV, Durban 4001, South Africa; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Adrie J C
authors.initials: AJ
authors.lastname: Steyn
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address: sychen@wh.iov.cn.
authors.forename: Shiyun
authors.initials: S
authors.lastname: Chen
mesh_terms: D000332:Aerobiosis / Q000235:genetics; D000595:Amino Acid Sequence; D000693:Anaerobiosis / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D005393:Fish Diseases / Q000382:microbiology / Q000473:pathology; D015964:Gene Expression Regulation, Bacterial; D006099:Granuloma / Q000382:microbiology / Q000473:pathology / Q000662:veterinary; D054884:Host-Pathogen Interactions; D007506:Iron-Sulfur Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009165:Mycobacterium Infections, Nontuberculous / Q000382:microbiology / Q000473:pathology; D019910:Mycobacterium marinum / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D018085:Regulon; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D014226:Triazenes / Q000737:chemistry / Q000494:pharmacology; D014774:Virulence; D015027:Zebrafish / Q000382:microbiology
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D001426:Bacterial Proteins; D007506:Iron-Sulfur Proteins; D020030:Nitric Oxide Donors; D014157:Transcription Factors; D014226:Triazenes; D009569:Nitric Oxide; D011494:Protein Kinases