title: Francisella tularensis suppresses the proinflammatory response of endothelial cells via the endothelial protein C receptor.
abstract: Various bacterial pathogens activate the endothelium to secrete proinflammatory cytokines and recruit circulating leukocytes. In contrast, there is a distinct lack of activation of these cells by Francisella tularensis, the causative agent of tularemia. Given the importance of endothelial cells in facilitating innate immunity, we investigated the ability of the attenuated live vaccine strain and virulent Schu S4 strain of F. tularensis to inhibit the proinflammatory response of HUVECs. Living F. tularensis live vaccine strain and Schu S4 did not stimulate secretion of the chemokine CCL2 by HUVECs, whereas material released from heat-killed bacteria did. Furthermore, the living bacteria suppressed secretion in response to heat-killed F. tularensis. This phenomenon was dose and contact dependent, and it occurred rapidly upon infection. The living bacteria did not inhibit the activation of HUVECs by Escherichia coli LPS, highlighting the specificity of this suppression. The endothelial protein C receptor (EPCR) confers anti-inflammatory properties when bound by activated protein C. When the EPCR was blocked, F. tularensis lost the ability to suppress activation of HUVECs. To our knowledge, this is the first report that a bacterial pathogen inhibits the host immune response via the EPCR. Endothelial cells are a critical component of the innate immune response to infection, and suppression of their activation by F. tularensis is likely a mechanism that aids in bacterial dissemination and evasion of host defenses.
authors.affiliation: Center for Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: DeAnna C
authors.initials: DC
authors.lastname: Bublitz
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Noah
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Benach
authors.forename: Martha B
authors.initials: MB
authors.lastname: Furie
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D000074283:Endothelial Protein C Receptor; D004797:Enzyme-Linked Immunosorbent Assay; D005604:Francisella tularensis / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018932:Chemokine CCL2; D000074283:Endothelial Protein C Receptor; D018836:Inflammation Mediators; D016209:Interleukin-8; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D014613:Vaccines, Attenuated