title: The receptor for the complement C3a anaphylatoxin (C3aR) provides host protection against Listeria monocytogenes-induced apoptosis.
abstract: Listeria monocytogenes is a Gram-positive intracellular bacterium that is acquired through tainted food and may lead to systemic infection and possible death. Despite the importance of the innate immune system in fighting L. monocytogenes infection, little is known about the role of complement and its activation products, including the potent C3a anaphylatoxin. In a model of systemic L. monocytogenes infection, we show that mice lacking the receptor for C3a (C3aR(-/-)) are significantly more sensitive to infection compared with wild-type mice, as demonstrated by decreased survival, increased bacterial burden, and increased damage to their livers and spleens. The inability of the C3aR(-/-) mice to clear the bacterial infection was not caused by defective macrophages or by a reduction in cytokines/chemokines known to be critical in the host response to L. monocytogenes, including IFN-γ and TNF-α. Instead, TUNEL staining, together with Fas, active caspase-3, and Bcl-2 expression data, indicates that the increased susceptibility of C3aR(-/-) mice to L. monocytogenes infection was largely caused by increased L. monocytogenes-induced apoptosis of myeloid and lymphoid cells in the spleen that are required for ultimate clearance of L. monocytogenes, including neutrophils, macrophages, dendritic cells, and T cells. These findings reveal an unexpected function of C3a/C3aR signaling during the host immune response that suppresses Fas expression and caspase-3 activity while increasing Bcl-2 expression, thereby providing protection to both myeloid and lymphoid cells against L. monocytogenes-induced apoptosis.
authors: Brown Foundation Institute of Molecular Medicine, Research Center for Immunology and Autoimmune Diseases, University of Texas Medical School at Houston, Houston, TX 77030; and.
authors: Stacey L
authors: SL
authors: Mueller-Ortiz
authors: Brown Foundation Institute of Molecular Medicine, Research Center for Immunology and Autoimmune Diseases, University of Texas Medical School at Houston, Houston, TX 77030; and.
authors: John E
authors: JE
authors: Morales
authors: Brown Foundation Institute of Molecular Medicine, Research Center for Immunology and Autoimmune Diseases, University of Texas Medical School at Houston, Houston, TX 77030; and Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030 Rick.A.Wetsel@uth.tmc.edu.
authors: Rick A
authors: RA
authors: Wetsel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008089:Listeria monocytogenes / Q000276:immunology* / Q000472:pathogenicity; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; C491899:Fas protein, mouse; D007166:Immunosuppressive Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011951:Receptors, Complement; C085567:complement C3a receptor; D019014:fas Receptor; D015926:Complement C3a; D053148:Caspase 3