Journal article
Francisella tularensis inhibits the intrinsic and extrinsic pathways to delay constitutive apoptosis and prolong human neutrophil lifespan
The Journal of immunology (1950), Vol.188(7), pp.3351-3363
04/01/2012
DOI: 10.4049/jimmunol.1102863
PMCID: PMC3311780
PMID: 22357630
Abstract
Francisella tularensis is a facultative intracellular bacterium that infects many cell types, including neutrophils. We demonstrated previously that F. tularensis inhibits NADPH oxidase assembly and activity and then escapes the phagosome to the cytosol, but effects on other aspects of neutrophil function are unknown. Neutrophils are short-lived cells that undergo constitutive apoptosis, and phagocytosis typically accelerates this process. We now demonstrate that F. tularensis significantly inhibited neutrophil apoptosis as indicated by morphologic analysis as well as annexin V and TUNEL staining. Thus, ∼80% of infected neutrophils remained viable at 48 h compared with ∼50% of control cells, and ∼40% of neutrophils that ingested opsonized zymosan. In keeping with this finding, processing and activation of procaspases-8, -9, and -3 were markedly diminished and delayed. F. tularensis also significantly impaired apoptosis triggered by Fas crosslinking. Of note, these effects were dose dependent and could be conferred by either intracellular or extracellular live bacteria, but not by formalin-killed organisms or isolated LPS and capsule, and were not affected by disruption of wbtA2 or FTT1236/FTL0708-genes required for LPS O-antigen and capsule biosynthesis. In summary, we demonstrate that F. tularensis profoundly impairs constitutive neutrophil apoptosis via effects on the intrinsic and extrinsic pathways, and thereby define a new aspect of innate immune evasion by this organism. As defects in neutrophil turnover prevent resolution of inflammation, our findings also suggest a mechanism that may in part account for the neutrophil accumulation, granuloma formation, and severe tissue damage that characterizes lethal pneumonic tularemia.
Details
- Title: Subtitle
- Francisella tularensis inhibits the intrinsic and extrinsic pathways to delay constitutive apoptosis and prolong human neutrophil lifespan
- Creators
- Justin T Schwartz - Inflammation Program, University of Iowa and the Veterans Administration Medical Center, Iowa City, IA 52242, USAJason H BarkerJustin KaufmanDrew C FayramJenna M McCrackenLee-Ann H Allen
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.188(7), pp.3351-3363
- DOI
- 10.4049/jimmunol.1102863
- PMID
- 22357630
- PMCID
- PMC3311780
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 AI073835-02 / NIAID NIH HHS R01 AI073835 / NIAID NIH HHS R01 AI073835-04 / NIAID NIH HHS T32 AI007511 / NIAID NIH HHS P01 AI044642-12 / NIAID NIH HHS I01 BX000513 / BLRD VA T32AI007511 / NIAID NIH HHS P01AI044642 / NIAID NIH HHS R01AI073835 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS P01 AI044642 / NIAID NIH HHS R01 AI073835-03 / NIAID NIH HHS
- Language
- English
- Date published
- 04/01/2012
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984094369802771
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