2. Academic Validation
  3. Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis

Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis

  • Nat Microbiol. 2017 May 15;2:17072. doi: 10.1038/nmicrobiol.2017.72.
Bibhuti B Mishra 1,  Rustin R Lovewell 1,  Andrew J Olive 1,  Guoliang Zhang 2,  Wenfei Wang 2,  Eliseo Eugenin 3,  Clare M Smith 1,  Jia Yao Phuah 1,  Jarukit E Long 1,  Michelle L Dubuke 4,  Samantha G Palace 1,  Jon D Goguen 1,  Richard E Baker 1,  Subhalaxmi Nambi 1,  Rabinarayan Mishra 5,  Matthew G Booty 1,  Christina E Baer 1,  Scott A Shaffer 4,  Veronique Dartois 3,  Beth A McCormick 1,  Xinchun Chen 2 6,  Christopher M Sassetti 1
Affiliations

Affiliations

  • 1 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • 2 Guangdong Key Lab of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen 518112, China.
  • 3 Public Health Research Institute Center at the International Center for Public Health, New Jersey Medical School - Rutgers, New Jersey 07103, USA.
  • 4 Proteomics and Mass Spectrometry Facility, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • 5 Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • 6 Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen 518060, China.
PMID: 28504669 DOI: 10.1038/nmicrobiol.2017.72
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.

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