Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media

ABSTRACT Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative, human-restricted pathogen. Although this bacterium typically colonizes the nasopharynx in the absence of clinical symptoms, it is also one of the major pathogens causing otitis media (OM) in children. Complement represents an imp...

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Autores principales:	Jeroen D. Langereis, Kim Stol, Elke K. Schweda, Brigitte Twelkmeyer, Hester J. Bootsma, Stefan P. W. de Vries, Peter Burghout, Dimitri A. Diavatopoulos, Peter W. M. Hermans
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/68261934a53d44799a991ac21bf5a7e8
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spelling	oai:doaj.org-article:68261934a53d44799a991ac21bf5a7e82021-11-15T15:39:09ZModified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media10.1128/mBio.00079-122150-7511https://doaj.org/article/68261934a53d44799a991ac21bf5a7e82012-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00079-12https://doaj.org/toc/2150-7511ABSTRACT Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative, human-restricted pathogen. Although this bacterium typically colonizes the nasopharynx in the absence of clinical symptoms, it is also one of the major pathogens causing otitis media (OM) in children. Complement represents an important aspect of the host defense against NTHi. In general, NTHi is efficiently killed by complement-mediated killing; however, various resistance mechanisms have also evolved. We measured the complement resistance of NTHi isolates isolated from the nasopharynx and the middle ear fluids of OM patients. Furthermore, we determined the molecular mechanism of NTHi complement resistance. Complement resistance was strongly increased in isolates from the middle ear, which correlated with decreased binding of IgM. We identified a crucial role for the R2866_0112 gene in complement resistance. Deletion of this gene altered the lipooligosaccharide (LOS) composition of the bacterium, which increased IgM binding and complement-mediated lysis. In a novel mouse model of coinfection with influenza virus, we demonstrate decreased virulence for the R2866_0112 deletion mutant. These findings identify a mechanism by which NTHi modifies its LOS structure to prevent recognition by IgM and activation of complement. Importantly, this mechanism plays a crucial role in the ability of NTHi to cause OM. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) colonizes the nasopharynx of especially young children without any obvious symptoms. However, NTHi is also a major pathogen in otitis media (OM), one of the most common childhood infections. Although this pathogen is often associated with OM, the mechanism by which this bacterium is able to cause OM is largely unknown. Our study addresses a key biological question that is highly relevant for child health: what is the molecular mechanism that enables NTHi to cause OM? We show that isolates collected from the middle ear fluid exhibit increased complement resistance and that the lipooligosaccharide (LOS) structure determines IgM binding and complement activation. Modification of the LOS structure decreased NTHi virulence in a novel NTHi-influenza A virus coinfection OM mouse model. Our findings may also have important implications for other Gram-negative pathogens harboring LOS, such as Neisseria meningitidis, Moraxella catarrhalis, and Bordetella pertussis.Jeroen D. LangereisKim StolElke K. SchwedaBrigitte TwelkmeyerHester J. BootsmaStefan P. W. de VriesPeter BurghoutDimitri A. DiavatopoulosPeter W. M. HermansAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 4 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Jeroen D. Langereis Kim Stol Elke K. Schweda Brigitte Twelkmeyer Hester J. Bootsma Stefan P. W. de Vries Peter Burghout Dimitri A. Diavatopoulos Peter W. M. Hermans Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
description	ABSTRACT Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative, human-restricted pathogen. Although this bacterium typically colonizes the nasopharynx in the absence of clinical symptoms, it is also one of the major pathogens causing otitis media (OM) in children. Complement represents an important aspect of the host defense against NTHi. In general, NTHi is efficiently killed by complement-mediated killing; however, various resistance mechanisms have also evolved. We measured the complement resistance of NTHi isolates isolated from the nasopharynx and the middle ear fluids of OM patients. Furthermore, we determined the molecular mechanism of NTHi complement resistance. Complement resistance was strongly increased in isolates from the middle ear, which correlated with decreased binding of IgM. We identified a crucial role for the R2866_0112 gene in complement resistance. Deletion of this gene altered the lipooligosaccharide (LOS) composition of the bacterium, which increased IgM binding and complement-mediated lysis. In a novel mouse model of coinfection with influenza virus, we demonstrate decreased virulence for the R2866_0112 deletion mutant. These findings identify a mechanism by which NTHi modifies its LOS structure to prevent recognition by IgM and activation of complement. Importantly, this mechanism plays a crucial role in the ability of NTHi to cause OM. IMPORTANCE Nontypeable Haemophilus influenzae (NTHi) colonizes the nasopharynx of especially young children without any obvious symptoms. However, NTHi is also a major pathogen in otitis media (OM), one of the most common childhood infections. Although this pathogen is often associated with OM, the mechanism by which this bacterium is able to cause OM is largely unknown. Our study addresses a key biological question that is highly relevant for child health: what is the molecular mechanism that enables NTHi to cause OM? We show that isolates collected from the middle ear fluid exhibit increased complement resistance and that the lipooligosaccharide (LOS) structure determines IgM binding and complement activation. Modification of the LOS structure decreased NTHi virulence in a novel NTHi-influenza A virus coinfection OM mouse model. Our findings may also have important implications for other Gram-negative pathogens harboring LOS, such as Neisseria meningitidis, Moraxella catarrhalis, and Bordetella pertussis.
format	article
author	Jeroen D. Langereis Kim Stol Elke K. Schweda Brigitte Twelkmeyer Hester J. Bootsma Stefan P. W. de Vries Peter Burghout Dimitri A. Diavatopoulos Peter W. M. Hermans
author_facet	Jeroen D. Langereis Kim Stol Elke K. Schweda Brigitte Twelkmeyer Hester J. Bootsma Stefan P. W. de Vries Peter Burghout Dimitri A. Diavatopoulos Peter W. M. Hermans
author_sort	Jeroen D. Langereis
title	Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
title_short	Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
title_full	Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
title_fullStr	Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
title_full_unstemmed	Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media
title_sort	modified lipooligosaccharide structure protects nontypeable <named-content content-type="genus-species">haemophilus influenzae</named-content> from igm-mediated complement killing in experimental otitis media
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/68261934a53d44799a991ac21bf5a7e8
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Modified Lipooligosaccharide Structure Protects Nontypeable <named-content content-type="genus-species">Haemophilus influenzae</named-content> from IgM-Mediated Complement Killing in Experimental Otitis Media

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