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 succ...
Main Authors: | , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
American Society for Microbiology
2018-01-01
|
Series: | mBio |
Online Access: | http://mbio.asm.org/cgi/content/full/9/1/e01755-17 |
id |
doaj-e787bbe51fa4490788ecc110f7fb57e5 |
---|---|
record_format |
Article |
spelling |
doaj-e787bbe51fa4490788ecc110f7fb57e52021-07-02T04:17:10ZengAmerican Society for MicrobiologymBio2150-75112018-01-0191e01755-1710.1128/mBio.01755-17Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease TreatmentJohannes B. HerrmannMarcel MuenstermannLea StrobelAlexandra Schubert-UnkmeirTrent M. WoodruffScott D. Gray-OwenAndreas KlosKay O. JohswichRino RappuoliSepsis 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.http://mbio.asm.org/cgi/content/full/9/1/e01755-17 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich Rino Rappuoli |
spellingShingle |
Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich Rino Rappuoli Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment mBio |
author_facet |
Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich Rino Rappuoli |
author_sort |
Johannes B. Herrmann |
title |
Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment |
title_short |
Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment |
title_full |
Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment |
title_fullStr |
Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment |
title_full_unstemmed |
Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment |
title_sort |
complement c5a receptor 1 exacerbates the pathophysiology of n. meningitidis sepsis and is a potential target for disease treatment |
publisher |
American Society for Microbiology |
series |
mBio |
issn |
2150-7511 |
publishDate |
2018-01-01 |
description |
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. |
url |
http://mbio.asm.org/cgi/content/full/9/1/e01755-17 |
work_keys_str_mv |
AT johannesbherrmann complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT marcelmuenstermann complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT leastrobel complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT alexandraschubertunkmeir complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT trentmwoodruff complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT scottdgrayowen complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT andreasklos complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT kayojohswich complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment AT rinorappuoli complementc5areceptor1exacerbatesthepathophysiologyofnmeningitidissepsisandisapotentialtargetfordiseasetreatment |
_version_ |
1721340521451880448 |