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In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa.

ABSTRACT: Neisseria meningitidis (Nme) asymptomatically colonizes the human nasopharynx, yet can initiate rapidly-progressing sepsis and meningitis in rare instances. Understanding the meningococcal lifestyle within the nasopharyngeal mucosa, a phase of infection that is prerequisite for disease, has been hampered by the lack of animal models. Herein, we compare mice expressing the four different human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that can bind the neisserial Opa protein adhesins, and find that expression of human CEACAM1 is necessary and sufficient to establish intranasal colonization. During infection, in vivo selection for phase variants expressing CEACAM1-specific Opa proteins occurs, allowing mucosal attachment and entry into the subepithelial space. Consistent with an essential role for Opa proteins in this process, Opa-deficient meningococci were unable to colonize the CEACAM1-humanized mice. While simple Opa-mediated attachment triggered an innate response regardless of meningococcal viability within the inoculum, persistence of viable Opa-expressing bacteria within the CEACAM1-humanized mice was required for a protective memory response to be achieved. Parenteral immunization with a capsule-based conjugate vaccine led to the accumulation of protective levels of Nme-specific IgG within the nasal mucus, yet the sterilizing immunity afforded by natural colonization was instead conferred by Nme-specific IgA without detectable IgG. Considered together, this study establishes that the availability of CEACAM1 helps define the exquisite host specificity of this human-restricted pathogen, displays a striking example of in vivo selection for the expression of desirable Opa variants, and provides a novel model in which to consider meningococcal infection and immunity within the nasopharyngeal mucosa.

SUBMITTER: Johswich KO

PROVIDER: S-EPMC3723569 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa.

Johswich Kay O KO McCaw Shannon E SE Islam Epshita E Sintsova Anna A Gu Angel A Shively John E JE Gray-Owen Scott D SD

PLoS pathogens 20130725 7

Neisseria meningitidis (Nme) asymptomatically colonizes the human nasopharynx, yet can initiate rapidly-progressing sepsis and meningitis in rare instances. Understanding the meningococcal lifestyle within the nasopharyngeal mucosa, a phase of infection that is prerequisite for disease, has been hampered by the lack of animal models. Herein, we compare mice expressing the four different human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that can bind the neisserial Opa prot ...[more]

PMID: 23935487

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Project description:Background: Expression of a capsule from one of serogroups A, B, C, W, X or Y is usually required for Neisseria meningitidis ( Nme) to cause invasive meningococcal disease. The capsule is encoded by the capsule locus, cps, which is proposed to have been acquired by a formerly capsule null organism by horizontal genetic transfer (HGT) from another species. Following identification of putative capsule genes in non-pathogenic Neisseria species, this hypothesis is re-examined. Methods: Whole genome sequence data from Neisseria species, including Nme genomes from a diverse range of clonal complexes and capsule genogroups, and non- Neisseria species, were obtained from PubMLST and GenBank. Sequence alignments of genes from the meningococcal cps, and predicted orthologues in other species, were analysed using Neighbor-nets, BOOTSCANing and maximum likelihood phylogenies. Results: The meningococcal cps was highly mosaic within regions B, C and D. A subset of sequences within regions B and C were phylogenetically nested within homologous sequences belonging to N. subflava, consistent with HGT event in which N. subflava was the donor. In the cps of 23/39 isolates, the two copies of region D were highly divergent, with rfbABC' sequences being more closely related to predicted orthologues in the proposed species N. weixii (GenBank accession number CP023429.1) than the same genes in Nme isolates lacking a capsule. There was also evidence of mosaicism in the rfbABC' sequences of the remaining 16 isolates, as well as rfbABC from many isolates. Conclusions: Data are consistent with the en bloc acquisition of cps in meningococci from N. subflava, followed by further recombination events with other Neisseria species. Nevertheless, the data cannot refute an alternative model, in which native meningococcal capsule existed prior to undergoing HGT with N. subflava and other species. Within-genus recombination events may have given rise to the diversity of meningococcal capsule serogroups.

Project description:UnlabelledNeisseria meningitidis colonizes the nasopharyngeal mucosa of healthy populations asymptomatically, although the bacterial surface is rich in motifs that activate the host innate immunity. What determines the tolerant host response to this bacterium in asymptomatic carriers is poorly understood. We demonstrated that the conserved meningococcal surface protein NhhA orchestrates monocyte (Mo) differentiation specifically into macrophage-like cells with a CD200R(hi) phenotype (NhhA-M?). In response to meningococcal stimulation, NhhA-M? failed to produce proinflammatory mediators. Instead, they upregulated interleukin-10 (IL-10) and Th2/regulatory T cell (Treg)-attracting chemokines, such as CCL17, CCL18, and CCL22. Moreover, NhhA-M? were highly efficient in eliminating bacteria. The in vivo validity of these findings was corroborated using a murine model challenged with N. meningitidis systematically or intranasally. The NhhA-modulated immune response protected mice from septic shock; Mo/M? depletion abolished this protective effect. Intranasal administration of NhhA induced an anti-inflammatory response, which was associated with N. meningitidis persistence at the nasopharynx. In vitro studies demonstrated that NhhA-triggered Mo differentiation occurred upon engaged Toll-like receptor 1 (TLR1)/TLR2 signaling and extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) activation and required endogenously produced IL-10 and tumor necrosis factor alpha (TNF-?). Our findings reveal a strategy that might be adopted by N. meningitidis to maintain asymptomatic nasopharyngeal colonization.ImportanceNeisseria meningitidis is an opportunistic human-specific pathogen that colonizes the nasopharyngeal mucosa asymptomatically in approximately 10% of individuals. Very little is known about how this bacterium evades immune activation during the carriage stage. Here, we observed that N. meningitidis, via the conserved surface protein NhhA, skewed monocyte differentiation into macrophages with a CD200R(hi) phenotype. Both in vivo and in vitro data demonstrated that these macrophages, upon meningococcal infection, played an important role in forming a homeostatic immune microenvironment through their capacity to eliminate invading bacteria and to generate anti-inflammatory mediators. This work provides novel insight into the mechanisms underlying the commensal persistence of N. meningitidis.

Dataset Information

In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa.

Publications

In vivo adaptation and persistence of Neisseria meningitidis within the nasopharyngeal mucosa.

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