title: Differential Contributions of the Complement Anaphylotoxin Receptors C5aR1 and C5aR2 to the Early Innate Immune Response against Staphylococcus aureus Infection.
abstract: The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1(-/)(-) mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2(-/)(-) mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum. Histological and immunohistochemistry investigation of infected kidneys at 24 h after bacterial inoculation revealed a discrete infiltration of neutrophils in wild type mice but already well-developed abscesses consisting of bacterial clusters surrounded by a large number of neutrophils in both C5aR1(-/)(-) and C5aR2(-/)(-) mice. Furthermore, blood neutrophils from C5aR1(-/)(-) mice were less efficient than those from wild type or C5aR2(-/)(-) mice at killing S. aureus. The requirement of C5aR1 for efficient killing of S. aureus was also demonstrated in human blood after disrupting C5a-C5aR1 signaling using specific inhibitors. These results demonstrated a role for C5aR1 in S. aureus clearance as well as a role for both C5aR1 and C5aR2 in the orchestration of the inflammatory response during infection.
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. sarah.horst@gmx.de.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Horst
authors.affiliation: Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. andreas.itzek@helmholtz-hzi.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Itzek
authors.affiliation: Institute of Medical Microbiology and Hospital Epidemiology, Medical School Hannover, Hannover, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. Klos.Andreas@mh-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Klos
authors.affiliation: Institute for Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany. andreas.beineke@tiho-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beineke
authors.affiliation: Infection Immunology Research Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. eva.medina@helmholtz-hzi.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Medina
keywords: C5a; C5aR1; C5aR2; Staphylococcus aureus; complement system; neutrophils