Nitric oxide prevents a pathogen permissive granulocytic inflammation during tuberculosis

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.

DOI: 10.1038/nmicrobiol.2017.72

Cite this paper

@inproceedings{Mishra2017NitricOP, title={Nitric oxide prevents a pathogen permissive granulocytic inflammation during tuberculosis}, author={Bibhuti Bhusan Mishra and Rustin R. Lovewell and Andrew J Olive and Guoliang Zhang and Wenfei Wang and Eliseo Alberto Eugenin and Clare M Smith and Jia Yao Phuah and Jarukit Edward Long and Michelle L. Dubuke and Samantha G. Palace and Jon D. Goguen and Richard E. Baker and Subhalaxmi Nambi and Rabinarayan Mishra and Matthew G Booty and Christina E. Baer and Scott A. Shaffer and V{\'e}ronique Dartois and Beth Ann McCormick and Xinchun Chen and Christopher M. Sassetti}, booktitle={Nature Microbiology}, year={2017} }