Journal article
Natural IgM mediates complement-dependent uptake of Francisella tularensis by human neutrophils via complement receptors 1 and 3 in nonimmune serum
The Journal of immunology (1950), Vol.189(6), pp.3064-3077
09/15/2012
DOI: 10.4049/jimmunol.1200816
PMCID: PMC3436988
PMID: 22888138
Abstract
A fundamental step in the life cycle of Francisella tularensis is bacterial entry into host cells. F. tularensis activates complement, and recent data suggest that the classical pathway is required for complement factor C3 deposition on the bacterial surface. Nevertheless, C3 deposition is inefficient and neither the specific serum components necessary for classical pathway activation by F. tularensis in nonimmune human serum nor the receptors that mediate infection of neutrophils have been defined. In this study, human neutrophil uptake of GFP-expressing F. tularensis strains live vaccine strain and Schu S4 was quantified with high efficiency by flow cytometry. Using depleted sera and purified complement components, we demonstrated first that C1q and C3 were essential for F. tularensis phagocytosis, whereas C5 was not. Second, we used purification and immunodepletion approaches to identify a critical role for natural IgM in this process, and then used a wbtA2 mutant to identify LPS O-Ag and capsule as prominent targets of these Abs on the bacterial surface. Finally, we demonstrate using receptor-blocking Abs that CR1 (CD35) and CR3 (CD11b/CD18) acted in concert for phagocytosis of opsonized F. tularensis by human neutrophils, whereas CR3 and CR4 (CD11c/CD18) mediated infection of human monocyte-derived macrophages. Altogether, our data provide fundamental insight into mechanisms of F. tularensis phagocytosis and support a model whereby natural IgM binds to surface capsular and O-Ag polysaccharides of F. tularensis and initiates the classical complement cascade via C1q to promote C3 opsonization of the bacterium and phagocytosis via CR3 and either CR1 or CR4 in a phagocyte-specific manner.
Details
- Title: Subtitle
- Natural IgM mediates complement-dependent uptake of Francisella tularensis by human neutrophils via complement receptors 1 and 3 in nonimmune serum
- Creators
- Justin T Schwartz - Inflammation Program, University of Iowa and Veterans Administration Medical Center, Iowa City, IA 52242, USAJason H BarkerMatthew E LongJustin KaufmanJenna McCrackenLee-Ann H Allen
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.189(6), pp.3064-3077
- DOI
- 10.4049/jimmunol.1200816
- PMID
- 22888138
- PMCID
- PMC3436988
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- T32-AI007511 / NIAID NIH HHS R01 AI073835 / NIAID NIH HHS T32 AI007511 / NIAID NIH HHS U54 AI057160-08 / NIAID NIH HHS R01AI073835-05 / NIAID NIH HHS U54 AI057160 / NIAID NIH HHS
- Language
- English
- Date published
- 09/15/2012
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984094539302771
Metrics
17 Record Views