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Antibody-Enhanced, Fc Gamma Receptor-Mediated Endocytosis of Clostridium difficile Toxin A
- Source :
- Infection and Immunity. 77:2294-2303
- Publication Year :
- 2009
- Publisher :
- American Society for Microbiology, 2009.
-
Abstract
- Toxin A (TcdA) and toxin B (TcdB) are major virulence factors of Clostridium difficile . These two toxins intoxicate cultured cells by similar mechanisms, and TcdB generally is more potent than TcdA in cultured cells. The exact reason for this difference is unclear. Here, we report that the cellular effects of TcdA can be substantially enhanced via an opsonizing antibody through Fc gamma receptor I (FcγRI)-mediated endocytosis. A TcdA-specific monoclonal antibody, A1H3, was found to significantly enhance the cytotoxicity of TcdA to macrophages and monocytes. The A1H3-dependent enhancement of glucosyltransferase activity, cytoskeleton disruption, and tumor necrosis factor alpha production induced by TcdA was further demonstrated using RAW 264.7 cells. Subsequent experiments indicated that the interaction of FcγRI with A1H3 underlays the antibody-dependent enhancement of the cellular effects of TcdA. While blocking FcγRII and FcγRIII with anti-CD16/32 antibodies did not affect the TcdA-mediated glucosylation of Rac1 in RAW 264.7 cells, presaturation of FcγRI with anti-CD64 antibodies in THP1 cells significantly reduced this activity. Incubation of a TcdA-A1H3 immune complex with recombinant mouse CD64 completely abrogated the A1H3-mediated enhancement of the glucosyltransferase activity of TcdA in RAW 264.7 cells. Moreover, expression of FcγRI in CHO cells strikingly enhanced the sensitivity of these cells to TcdA complexed with A1H3. We showed that the presence of A1H3 facilitated cell surface recruitment of TcdA, contributing to the antibody-dependent, FcγRI-mediated enhancement of TcdA activity. Finally, studies using chlorpromazine and endosomal acidification inhibitors revealed an important role of the endocytic pathway in the A1H3-dependent enhancement of TcdA activity.
- Subjects :
- rac1 GTP-Binding Protein
Glycosylation
medicine.drug_class
Bacterial Toxins
Immunology
Clostridium difficile toxin A
Clostridium difficile toxin B
Endocytosis
Monoclonal antibody
Microbiology
Cell Line
Enterotoxins
Mice
medicine
Animals
Humans
Cytotoxicity
Cellular Microbiology: Pathogen-Host Cell Molecular Interactions
biology
Clostridioides difficile
Macrophages
Neuropeptides
Receptors, IgG
Antibodies, Monoclonal
Antibodies, Bacterial
Molecular biology
rac GTP-Binding Proteins
Rac GTP-Binding Proteins
Infectious Diseases
Cell culture
biology.protein
Parasitology
Antibody
Subjects
Details
- ISSN :
- 10985522 and 00199567
- Volume :
- 77
- Database :
- OpenAIRE
- Journal :
- Infection and Immunity
- Accession number :
- edsair.doi.dedup.....e501b36868e5ff8d2de33055a2d9a162