Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis

Bibhuti B. Mishra, Rustin R. Lovewell, Andrew J. Olive, Guoliang Zhang, Wenfei Wang, Eliseo Eugenin, Clare M. Smith, Jia Yao Phuah, Jarukit E. Long, Michelle L. Dubuke, Samantha G. Palace, Jon D. Goguen, Richard E. Baker, Subhalaxmi Nambi, Rabinarayan Mishra, Matthew G. Booty, Christina E. Baer, Scott A. Shaffer, Veronique Dartois, Beth A. McCormickXinchun Chen, Christopher M. Sassetti

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Nitric oxide contributes to protection from tuberculosis. It is generally assumed that this protection is due to direct inhibition of Mycobacterium tuberculosis growth, which prevents subsequent pathological inflammation. In contrast, we report that nitric oxide primarily protects mice by repressing an interleukin-1- and 12/15-lipoxygenase-dependent neutrophil recruitment cascade that promotes bacterial replication. Using M. tuberculosis mutants as indicators of the pathogen's environment, we inferred that granulocytic inflammation generates a nutrient-replete niche that supports M. tuberculosis growth. Parallel clinical studies indicate that a similar inflammatory pathway promotes tuberculosis in patients. The human 12/15-lipoxygenase orthologue, ALOX12, is expressed in cavitary tuberculosis lesions; the abundance of its products correlates with the number of airway neutrophils and bacterial burden and a genetic polymorphism that increases ALOX12 expression is associated with tuberculosis risk. These data suggest that M. tuberculosis exploits neutrophilic inflammation to preferentially replicate at sites of tissue damage that promote contagion.

Original languageEnglish (US)
Article number17072
JournalNature Microbiology
Volume2
DOIs
StatePublished - May 15 2017

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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  • Cite this

    Mishra, B. B., Lovewell, R. R., Olive, A. J., Zhang, G., Wang, W., Eugenin, E., Smith, C. M., Phuah, J. Y., Long, J. E., Dubuke, M. L., Palace, S. G., Goguen, J. D., Baker, R. E., Nambi, S., Mishra, R., Booty, M. G., Baer, C. E., Shaffer, S. A., Dartois, V., ... Sassetti, C. M. (2017). Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nature Microbiology, 2, [17072]. https://doi.org/10.1038/nmicrobiol.2017.72