Platelet-Activating Factor Receptor and Innate Immunity: Uptake of Gram-Positive Bacterial Cell Wall into Host Cells and Cell-Specific Pathophysiology

• Published in: Journal of Immunology 2006-11, Vol.177 (9), p.6182-6191
• Main Authors: Fillon, Sophie, Soulis, Konstantinos, Rajasekaran, Surender, Benedict-Hamilton, Heather, Radin, Jana N, Orihuela, Carlos J, El Kasmi, Karim C, Murti, Gopal, Kaushal, Deepak, Gaber, M. Waleed, Weber, Joerg R, Murray, Peter J, Tuomanen, Elaine I
• Format: Article
• Language: English
• Subjects: Animals; Bacteria; Cell Wall - chemistry; Cell Wall - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; Endothelium, Vascular - microbiology; Gram-Positive Bacteria - immunology; Immunity, Innate - genetics; Mice; Mice, Mutant Strains; Myocytes, Cardiac - metabolism; Neurons - metabolism; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - physiology; Phosphorylcholine - analysis; Platelet Membrane Glycoproteins - genetics; Platelet Membrane Glycoproteins - physiology; Pneumococcal Infections - immunology; Pneumococcal Infections - microbiology; Pneumococcal Infections - physiopathology; Rats; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - physiology; Streptococcus pneumoniae - immunology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - physiology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.177.9.6182

The current model of innate immune recognition of Gram-positive bacteria suggests that the bacterial cell wall interacts with host recognition proteins such as TLRs and Nod proteins. We describe an additional recognition system mediated by the platelet-activating factor receptor (PAFr) and directed to the pathogen-associated molecular pattern phosphorylcholine that results in the uptake of bacterial components into host cells. Intravascular choline-containing cell walls bound to endothelial cells and caused rapid lethality in wild-type, Tlr2(-/-), and Nod2(-/-) mice but not in Pafr(-/-) mice. The cell wall exited the vasculature into the heart and brain, accumulating within endothelial cells, cardiomyocytes, and neurons in a PAFr-dependent way. Physiological consequences of the cell wall/PAFr interaction were cell specific, being noninflammatory in endothelial cells and neurons but causing a rapid loss of cardiomyocyte contractility that contributed to death. Thus, PAFr shepherds phosphorylcholine-containing bacterial components such as the cell wall into host cells from where the response ranges from quiescence to severe pathophysiology.