Platelet-activating factor receptor and innate immunity: uptake of gram-positive bacterial cell wall into host cells and cell-specific pathophysiology.
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.
Fillon
Sophie
S
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105, USA.
Soulis
Konstantinos
K
Rajasekaran
Surender
S
Benedict-Hamilton
Heather
H
Radin
Jana N
JN
Orihuela
Carlos J
CJ
El Kasmi
Karim C
KC
Murti
Gopal
G
Kaushal
Deepak
D
Gaber
M Waleed
MW
Weber
Joerg R
JR
Murray
Peter J
PJ
Tuomanen
Elaine I
EI
D000818:Animals; D002473:Cell Wall / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000382:microbiology; D006094:Gram-Positive Bacteria / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000502:physiology; D010767:Phosphorylcholine / Q000032:analysis; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011008:Pneumococcal Infections / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D013296:Streptococcus pneumoniae / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology
D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C039351:platelet activating factor receptor; D010767:Phosphorylcholine