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Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages.

Neutrophils are typically the first responders in host defense against invading pathogens, which they destroy by both oxidative and nonoxidative mechanisms. However, despite a longstanding recognition of neutrophil presence at disease sites in tuberculosis, their role in defense against mycobacteria is unclear. Here we exploit the genetic tractability and optical transparency of zebrafish to monitor neutrophil behavior and its consequences during infection with Mycobacterium marinum, a natural fish pathogen. In contrast to macrophages, neutrophils do not interact with mycobacteria at initial infection sites. Neutrophils are subsequently recruited to the nascent granuloma in response to signals from dying infected macrophages within the granuloma, which they phagocytose. Some neutrophils then rapidly kill the internalized mycobacteria through NADPH oxidase-dependent mechanisms. Our results provide a mechanistic link to the observed patterns of neutrophils in human tuberculous granulomas and the susceptibility of humans with chronic granulomatous disease to mycobacterial infection.

Pubmed ID: 22980327

Authors

  • Yang CT
  • Cambier CJ
  • Davis JM
  • Hall CJ
  • Crosier PS
  • Ramakrishnan L

Journal

Cell host & microbe

Publication Data

September 13, 2012

Associated Grants

  • Agency: NIMH NIH HHS, Id: DP1 MH099901
  • Agency: PHS HHS, Id: R01 A136396
  • Agency: PHS HHS, Id: R01 A154503
  • Agency: NIAID NIH HHS, Id: R01 AI036396
  • Agency: NIAID NIH HHS, Id: R37 AI054503

Mesh Terms

  • Animals
  • Granuloma
  • Humans
  • Macrophages
  • Microbial Viability
  • Molecular Sequence Data
  • Mycobacterium marinum
  • NADP
  • Neutrophils
  • Oxidation-Reduction
  • Oxidative Stress
  • Oxidoreductases
  • Sequence Analysis, DNA
  • Zebrafish