17579
2018
eng
e01755-17
1
9
article
1
2019-02-01
--
--
Complement C5a receptor 1 exacerbates the pathophysiology of N. meningitidis sepsis and is a potential target for disease treatment
Sepsis caused by Neisseria meningitidis (meningococcus) is a rapidly progressing, life-threatening disease. Because its initial symptoms are rather unspecific, medical attention is often sought too late, i.e., when the systemic inflammatory response is already unleashed. This in turn limits the success of antibiotic treatment. The complement system is generally accepted as the most important innate immune determinant against invasive meningococcal disease since it protects the host through the bactericidal membrane attack complex. However, complement activation concomitantly liberates the C5a peptide, and it remains unclear whether this potent anaphylatoxin contributes to protection and/or drives the rapidly progressing immunopathogenesis associated with meningococcal disease. Here, we dissected the specific contribution of C5a receptor 1 (C5aR1), the canonical receptor for C5a, using a mouse model of meningococcal sepsis. Mice lacking C3 or C5 displayed susceptibility that was enhanced by >1,000-fold or 100-fold, respectively, consistent with the contribution of these components to protection. In clear contrast, C5ar1\(^{-/-}\) mice resisted invasive meningococcal infection and cleared N. meningitidis more rapidly than wild-type (WT) animals. This favorable outcome stemmed from an ameliorated inflammatory cytokine response to N. meningitidis in C5ar1\(^{-/-}\) mice in both in vivo and ex vivo whole-blood infections. In addition, inhibition of C5aR1 signaling without interference with the complement bactericidal activity reduced the inflammatory response also in human whole blood. Enticingly, pharmacologic C5aR1 blockade enhanced mouse survival and lowered meningococcal burden even when the treatment was administered after sepsis induction. Together, our findings demonstrate that C5aR1 drives the pathophysiology associated with meningococcal sepsis and provides a promising target for adjunctive therapy.
Importance:
The devastating consequences of N. meningitidis sepsis arise due to the rapidly arising and self-propagating inflammatory response that mobilizes antibacterial defenses but also drives the immunopathology associated with meningococcemia. The complement cascade provides innate broad-spectrum protection against infection by directly damaging the envelope of pathogenic microbes through the membrane attack complex and triggers an inflammatory response via the C5a peptide and its receptor C5aR1 aimed at mobilizing cellular effectors of immunity. Here, we consider the potential of separating the bactericidal activities of the complement cascade from its immune activating function to improve outcome of N. meningitidis sepsis. Our findings demonstrate that the specific genetic or pharmacological disruption of C5aR1 rapidly ameliorates disease by suppressing the pathogenic inflammatory response and, surprisingly, allows faster clearance of the bacterial infection. This outcome provides a clear demonstration of the therapeutic benefit of the use of C5aR1-specific inhibitors to improve the outcome of invasive meningococcal disease.
mBio
10.1128/mBio.01755-17
urn:nbn:de:bvb:20-opus-175792
mBio 2018, Volume 9, Issue 1, e01755-17. DOI: 10.1128/mBio.01755-17
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Johannes Herrmann
Marcel Muenstermann
Lea Strobel
Alexandra Schubert-Unkmeir
Trent M. Woodruff
Scott D. Gray-Owen
Andreas Klos
Kay O. Johswich
eng
uncontrolled
C5aR1
eng
uncontrolled
whole-blood model
eng
uncontrolled
Neisseria meningitidis
eng
uncontrolled
anaphylatoxins
eng
uncontrolled
complement system
eng
uncontrolled
inflammation
eng
uncontrolled
invasive disease
eng
uncontrolled
mouse model
eng
uncontrolled
neutrophils
eng
uncontrolled
sepsis
Biowissenschaften; Biologie
open_access
Institut für Hygiene und Mikrobiologie
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17579/Herrmann_mBio.pdf
20049
2019
eng
677-694
1
10
article
1
2020-03-05
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--
Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections
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 (A8\(^{Δ71−73}\)) 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.
Virulence
10.1080/21505594.2019.1640035
urn:nbn:de:bvb:20-opus-200496
Virulence 2019, Vol. 10, No. 1, 677-694. DOI: 10.1080/21505594.2019.1640035
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Marcel Muenstermann
Lea Strobel
Andreas Klos
Rick A. Wetsel
Trent M. Woodruff
Jörg Köhl
Kay O. Johswich
eng
uncontrolled
inflammation
eng
uncontrolled
C3a
eng
uncontrolled
C5a
eng
uncontrolled
C3aR
eng
uncontrolled
C5aR1
eng
uncontrolled
C5aR2
eng
uncontrolled
meningococcal disease
eng
uncontrolled
sepsis
Medizin und Gesundheit
open_access
Institut für Hygiene und Mikrobiologie
Förderzeitraum 2019
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20049/Muenstermann_Virulence.pdf