Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis
Department of Microbiology and Physiological Systems; Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology; Department of Pathology; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Microbiology | Molecular Biology
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.
Antimicrobial responses, Bacterial host response, Bacterial pathogenesis, Tuberculosis
DOI of Published Version
Nat Microbiol. 2017 May 15;2:17072. doi: 10.1038/nmicrobiol.2017.72. Link to article on publisher's site
Mishra, Bibhuti B.; Lovewell, Rustin R.; Olive, Andrew J.; Smith, Clare M.; Phuah, Jia Yao; Long, Jarukit E.; Dubuke, Michelle L.; Palace, Samantha G.; Goguen, Jon D.; Baker, Richard E.; Nambi, Subhalaxmi; Mishra, Rabinarayan; Booty, Matthew G.; Baer, Christina E.; Shaffer, Scott A.; McCormick, Beth A.; and Sassetti, Christopher M., "Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis" (2017). UMass Metabolic Network Publications. 114.