title: Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages.
abstract: 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.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Chao-Tsung
authors.initials: CT
authors.lastname: Yang
authors.forename: C J
authors.initials: CJ
authors.lastname: Cambier
authors.forename: J Muse
authors.initials: JM
authors.lastname: Davis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hall
authors.forename: Philip S
authors.initials: PS
authors.lastname: Crosier
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D006099:Granuloma / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects*; D008969:Molecular Sequence Data; D019910:Mycobacterium marinum / Q000187:drug effects / Q000276:immunology*; D009249:NADP / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000276:immunology / Q000382:microbiology
chemical_list: D009249:NADP; D010088:Oxidoreductases