Aggregatibacter actinomycetemcomitans Leukotoxin (LtxA) Requires Death Receptor Fas, in Addition to LFA-1, To Trigger Cell Death in T Lymphocytes
| Autor: | Liam T. Schober, Brian A. Vega, Tami Kim, Scott C. Kachlany, Benjamin A. Belinka |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Programmed cell death Virulence Factors Lymphocyte T-Lymphocytes Immunology Integrin Exotoxins Biology Microbiology Jurkat cells Virulence factor Fas ligand 03 medical and health sciences Jurkat Cells 0302 clinical medicine medicine Humans CD11a Antigen fas Receptor Receptor Cellular Microbiology: Pathogen-Host Cell Molecular Interactions Cell Death Aggregatibacter actinomycetemcomitans hemic and immune systems 030206 dentistry biology.organism_classification Lymphocyte Function-Associated Antigen-1 030104 developmental biology Infectious Diseases medicine.anatomical_structure CD18 Antigens Caspases biology.protein Cancer research Parasitology |
| Zdroj: | Infection and immunity. 87(8) |
| ISSN: | 1098-5522 |
| Popis: | Leukotoxin (LtxA) (trade name, Leukothera) is a protein secreted by the oral bacterium Aggregatibacter actinomycetemcomitans. A. actinomycetemcomitans is an oral pathogen strongly associated with development of localized aggressive periodontitis. LtxA acts as a virulence factor for A. actinomycetemcomitans by binding to the β2 integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) on white blood cells (WBCs) and causing cell death. In addition, because of its specificity for malignant and activated WBCs, LtxA is being investigated as a therapeutic agent for treatment of hematological malignancies and autoimmune diseases. Here, we report the successful generation and characterization of Jurkat T lymphocytes with deletions in CD18, CD11a, and Fas that were engineered using CRISPR/Cas9 gene editing. Using these clones, we demonstrate the specificity of LtxA for cells expressing LFA-1. We also demonstrate the requirement of the cell death receptor Fas for LtxA-mediated cell death in T lymphocytes. We show that LFA-1 and Fas are early events in the LtxA-mediated cell death cascade as caspase activation and mitochondrial perturbation do not occur in the absence of either receptor. To our knowledge, LtxA is the first molecule, other than FasL, known to require the Fas death receptor to initiate cell death. Knowledge of the mechanism of cell death induced by LtxA will facilitate the understanding of LtxA as a bacterial virulence factor and development of it as a potential therapeutic agent. |
| Databáze: | OpenAIRE |
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