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Virulence. 2019 Dec;10(1):677-694. doi: 10.1080/21505594.2019.1640035.

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections.

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a Institut für Hygiene und Mikrobiologie , Universität Würzburg , Würzburg , Germany.
b Institut für Medizinische Mikrobiologie und Krankenhaushygiene , Medizinische Hochschule Hannover , Hannover , Germany.
c Institute of Molecular Medicine Center for Immunology and Autoimmune Diseases , The University of Texas Health Science Center , Houston , TX , USA.
d School of Biomedical Sciences , The University of Queensland , Brisbane , Australia.
e Institute for Systemic Inflammation Research , University of Lübeck , Lübeck , Germany.
f Division of Immunobiology , Cincinnati Children's Hospital and University of Cincinnati College of Medicine , Cincinnati , OH , USA.


The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar-/- mice, whereas C5ar1-/- and C5ar2-/- mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1-/- mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8Δ71-73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.


C3a; C3aR; C5a; C5aR1; C5aR2; inflammation; meningococcal disease; sepsis

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