Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis

Ramona L McCaffrey; Justin T Schwartz; Stephen R Lindemann; Jessica G Moreland; Blake W Buchan; Bradley D Jones; Lee-Ann H Allen

doi:10.1189/jlb.1209811

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Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis

Journal article

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Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis

Ramona L McCaffrey, Justin T Schwartz, Stephen R Lindemann, Jessica G Moreland, Blake W Buchan, Bradley D Jones and Lee-Ann H Allen

Journal of leukocyte biology, Vol.88(4), pp.791-805

10/2010

DOI: 10.1189/jlb.1209811

PMCID: PMC2974429

PMID: 20610796

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Abstract

Francisella tularensis uses both pre- and post-assembly mechanisms to inhibit NADPH oxidase activity at its own phagosome and throughout infected human neutrophils. Ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft-mediated NADPH oxidase inhibition is more complex than appreciated previously. We confirm that phagosomes containing Ft opsonized with AS exclude flavocytochrome b 558 and extend previous results to show that soluble phox proteins were also affected, as indicated by diminished phosphorylation of p47 phox and other PKC substrates. However, a different mechanism accounts for the ability of Ft to inhibit neutrophil activation by formyl peptides, Staphylococcus aureus , OpZ, and phorbol esters. In this case, enzyme targeting and assembly were normal, and impaired superoxide production was characterized by sustained membrane accumulation of dysfunctional NADPH oxidase complexes. A similar post-assembly inhibition mechanism also diminished the ability of anti-Ft IS to confer neutrophil activation and bacterial killing, consistent with the limited role for antibodies in host defense during tularemia. Studies of mutants that we generated in the type A Ft strain Schu S4 demonstrate that the regulatory factor fevR is essential for NADPH oxidase inhibition, whereas iglI and iglJ, candidate secretion system effectors, and the acid phosphatase acpA are not. As Ft uses multiple mechanisms to block neutrophil NADPH oxidase activity, our data strongly suggest that this is a central aspect of virulence.

pathogenesis

tularemia

immune serum

respiratory burst

Host Defense & Pathophysiology

neutrophil

phosphorylation

Details

Title: Subtitle: Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis
Creators: Ramona L McCaffrey - Inflammation Program and
Justin T Schwartz - Inflammation Program and
Stephen R Lindemann - Microbiology, and
Jessica G Moreland - Inflammation Program and
Blake W Buchan - Microbiology, and
Bradley D Jones - Microbiology, and
Lee-Ann H Allen - Inflammation Program and
Resource Type: Journal article
Publication Details: Journal of leukocyte biology, Vol.88(4), pp.791-805
Publisher: Society for Leukocyte Biology
DOI: 10.1189/jlb.1209811
PMID: 20610796
PMCID: PMC2974429
ISSN: 0741-5400
eISSN: 1938-3673
Language: English
Date published: 10/2010
Academic Unit: Microbiology and Immunology; Infectious Diseases; Internal Medicine
Record Identifier: 9984083274102771

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