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Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage of Neisseria meningitidis
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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2016 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, no 1, e01670-15Article in journal (Refereed) Published
Abstract [en]

Neisseria 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 CD200Rhi phenotype (NhhA-MΦ). In response to meningococcal stimulation, NhhA-MΦ failed to produce proinflammatory mediators. Instead, they upregulated IL-10 and Th2/Treg-attracting chemokines, such as CCL-17, CCL-18, and CCL-22. Moreover, NhhA-MΦ cells 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. NhhA-modulated immune response protected mice from septic shock; Mo/MΦ 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 (TLR)1/TLR2 signaling and ERK and JNK activation and required endogenously produced IL-10 and TNF-α. Our findings reveal a strategy that might be adopted by N. meningitidis to maintain asymptomatic nasopharyngeal colonization.

Place, publisher, year, edition, pages
2016. Vol. 7, no 1, e01670-15
National Category
Immunology Microbiology
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-129123DOI: 10.1128/mBio.01670-15ISI: 000373933100067OAI: oai:DiVA.org:su-129123DiVA: diva2:919750
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2016-05-09Bibliographically approved
In thesis
1. Macrophage programming and host responses to bacterial infection
Open this publication in new window or tab >>Macrophage programming and host responses to bacterial infection
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Macrophages are dynamic, plastic, and heterogeneous immune cells that play an important role in host immune defense against bacterial infection. Various bacterial pathogens, such as Neisseria meningitidis and Mycobacterium tuberculosis, can modulate host immune responses by interfering with macrophage differentiation and polarization.

The focus of this thesis was to understand the role of macrophages in the pathogenesis of bacteria-induced diseases, which has important implications in the search for novel therapeutic strategies to control those infectious diseases.

In Paper I, we found that NhhA, a conserved meningococcal outer membrane protein, can activate macrophages through both Toll-like receptor 4 (TLR4)-dependent and -independent pathways. In Paper II, we demonstrated that NhhA activates monocytes through TLR2 and triggers autocrine IL-10 and TNF production through the ERK and JNK pathways, which skew monocyte differentiation into CD200Rhi macrophages. These immune homeostatic macrophages are associated with nasopharyngeal carriage of meningococci. In Paper III, we examined the role of human CD46, a ubiquitous transmembrane protein, in regulating macrophage apoptosis, differentiation, and functional polarization. We revealed that macrophages expressing CD46 exhibit an M1 phenotype and are prone to generate proinflammatory cytokines, such as IL-6, TNF, and IL-12, upon lipopolysaccharide challenge or meningococcal infection. The important role of these macrophages in the development of septic shock was further confirmed by in vivo studies using a CD46 transgenic mouse disease model. M. tuberculosis, a gram-positive bacterium, remains an important cause of death in developing countries. In Paper IV, we reported that murine macrophages expressing human CD46 exhibit enhanced viability and bactericidal capacity and are prone to form granulomas following chronic mycobacterial infection. Increased understanding of host factor roles in the physiopathology of tuberculosis is critical for the design of effective vaccines and new drugs.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. 51 p.
Keyword
Macrophages, meningococci, mycobacteria, NhhA, CD46, cytokines
National Category
Immunology Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-129243 (URN)978-91-7649-426-4 (ISBN)
Public defence
2016-06-09, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrehnius väg 20, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2016-05-17 Created: 2016-04-18 Last updated: 2016-05-09Bibliographically approved

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