5′-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice

Ryan H. Senaratne, A. Dharshan De Silva, Spencer J. Williams, Joseph D. Mougous, J. Rachel Reader, Tianjiao Zhang, Stephen Chan, Ben Sidders, Dong H. Lee, John Chan, Carolyn R. Bertozzi, Lee W. Riley

Research output: Contribution to journalArticle

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Abstract

A major obstacle to tuberculosis (TB) control is the problem of chronic TB infection (CTBI). Here we report that 5′-adenosinephosphosulphate reductase (CysH), an enzyme essential for the production of reduced-sulphur- containing metabolites, is critical for Mycobacterium tuberculosis (Mtb) survival in chronic infection phase in mice. Disruption of cysH rendered Mtb auxotrophic for cysteine and methionine, and attenuated virulence in BALB/c and C57BL/6 immunocompetent mice. The mutant and wild-type Mtb replicated similarly during the acute phase of infection, but the mutant showed reduced viability during the persistent phase of the infection. The cysH mutant caused disease and death after 4-7 weeks of infection in four different groups of mice - Rag1 -/-, NOS2-/-, gp91phox-/- NOS2-/- and gp91phox-/- mice given aminoguanidine [to suppress the effects of nitric oxide synthase 2 (NOS2)]- indicating minimal metabolic effect on the cysH mutant survival in these mice. The cysH mutant was also susceptible to peroxynitrite and hydrogen peroxide in vitro. These results show that CysH is important for Mtb protection during the chronic infection phase, and that resistance to nitrosative and oxidative stress may be the mechanism of this protection. Thus, this metabolic gene of an intracellular pathogen could have a secondary role in protection against the host immune response. Finally the lack of an endogenous human orthologue of cysH and its possible role in defence against adaptive immunity renders CysH an attractive enzyme for further studies as a target for therapeutics active against CTBI.

Original languageEnglish (US)
Pages (from-to)1744-1753
Number of pages10
JournalMolecular Microbiology
Volume59
Issue number6
DOIs
StatePublished - Mar 2006

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Mycobacterium tuberculosis
Free Radicals
Oxidoreductases
Infection
Nitric Oxide Synthase
Tuberculosis
Peroxynitrous Acid
Survival
Adaptive Immunity
Enzymes
Sulfur
Methionine
Hydrogen Peroxide
Cysteine
Virulence
Oxidative Stress
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology

Cite this

5′-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice. / Senaratne, Ryan H.; De Silva, A. Dharshan; Williams, Spencer J.; Mougous, Joseph D.; Reader, J. Rachel; Zhang, Tianjiao; Chan, Stephen; Sidders, Ben; Lee, Dong H.; Chan, John; Bertozzi, Carolyn R.; Riley, Lee W.

In: Molecular Microbiology, Vol. 59, No. 6, 03.2006, p. 1744-1753.

Research output: Contribution to journalArticle

Senaratne, RH, De Silva, AD, Williams, SJ, Mougous, JD, Reader, JR, Zhang, T, Chan, S, Sidders, B, Lee, DH, Chan, J, Bertozzi, CR & Riley, LW 2006, '5′-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice', Molecular Microbiology, vol. 59, no. 6, pp. 1744-1753. https://doi.org/10.1111/j.1365-2958.2006.05075.x
Senaratne, Ryan H. ; De Silva, A. Dharshan ; Williams, Spencer J. ; Mougous, Joseph D. ; Reader, J. Rachel ; Zhang, Tianjiao ; Chan, Stephen ; Sidders, Ben ; Lee, Dong H. ; Chan, John ; Bertozzi, Carolyn R. ; Riley, Lee W. / 5′-Adenosinephosphosulphate reductase (CysH) protects Mycobacterium tuberculosis against free radicals during chronic infection phase in mice. In: Molecular Microbiology. 2006 ; Vol. 59, No. 6. pp. 1744-1753.
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AU - Reader, J. Rachel

AU - Zhang, Tianjiao

AU - Chan, Stephen

AU - Sidders, Ben

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