Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment

ABSTRACT 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...

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Autores principales:	Johannes B. Herrmann, Marcel Muenstermann, Lea Strobel, Alexandra Schubert-Unkmeir, Trent M. Woodruff, Scott D. Gray-Owen, Andreas Klos, Kay O. Johswich
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	C5aR1 Neisseria meningitidis anaphylatoxins complement system inflammation invasive disease Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8d5ddfe44f84454f96d7562df509f7ab
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spelling	oai:doaj.org-article:8d5ddfe44f84454f96d7562df509f7ab2021-11-15T15:53:25ZComplement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment10.1128/mBio.01755-172150-7511https://doaj.org/article/8d5ddfe44f84454f96d7562df509f7ab2018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01755-17https://doaj.org/toc/2150-7511ABSTRACT 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.Johannes B. HerrmannMarcel MuenstermannLea StrobelAlexandra Schubert-UnkmeirTrent M. WoodruffScott D. Gray-OwenAndreas KlosKay O. JohswichAmerican Society for MicrobiologyarticleC5aR1Neisseria meningitidisanaphylatoxinscomplement systeminflammationinvasive diseaseMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	C5aR1 Neisseria meningitidis anaphylatoxins complement system inflammation invasive disease Microbiology QR1-502
spellingShingle	C5aR1 Neisseria meningitidis anaphylatoxins complement system inflammation invasive disease Microbiology QR1-502 Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
description	ABSTRACT 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.
format	article
author	Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich
author_facet	Johannes B. Herrmann Marcel Muenstermann Lea Strobel Alexandra Schubert-Unkmeir Trent M. Woodruff Scott D. Gray-Owen Andreas Klos Kay O. Johswich
author_sort	Johannes B. Herrmann
title	Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
title_short	Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
title_full	Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
title_fullStr	Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
title_full_unstemmed	Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment
title_sort	complement c5a receptor 1 exacerbates the pathophysiology of <italic toggle="yes">n. meningitidis</italic> sepsis and is a potential target for disease treatment
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/8d5ddfe44f84454f96d7562df509f7ab
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Complement C5a Receptor 1 Exacerbates the Pathophysiology of <italic toggle="yes">N. meningitidis</italic> Sepsis and Is a Potential Target for Disease Treatment

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