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Macrophage programming and host responses to bacterial infection
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Hong Sjölinder)
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 [en]
Macrophages, meningococci, mycobacteria, NhhA, CD46, cytokines
National Category
Immunology Microbiology
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-129243ISBN: 978-91-7649-426-4 (print)OAI: oai:DiVA.org:su-129243DiVA: diva2:920447
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: 2017-02-24Bibliographically approved
List of papers
1. The Meningococcal Adhesin NhhA Provokes Proinflammatory Responses in Macrophages via Toll-Like Receptor 4-Dependent and -Independent Pathways
Open this publication in new window or tab >>The Meningococcal Adhesin NhhA Provokes Proinflammatory Responses in Macrophages via Toll-Like Receptor 4-Dependent and -Independent Pathways
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2012 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 80, no 11, 4027-4033 p.Article in journal (Refereed) Published
Abstract [en]

Activation of macrophages by Toll-like receptors (TLRs) and functionally related proteins is essential for host defense and innate immunity. TLRs recognize a wide variety of pathogen-associated molecules. Here, we demonstrate that the meningococcal outer membrane protein NhhA has immunostimulatory functions and triggers release of proinflammatory cytokines from macrophages. NhhA-induced cytokine release was found to proceed via two distinct pathways in RAW 264.7 macrophages. Interleukin-6 (IL-6) secretion was dependent on activation of TLR4 and required the TLR signaling adaptor protein MyD88. In contrast, release of tumor necrosis factor (TNF) was TLR4 and MyD88 independent. Both pathways involved NF-kappa B-dependent gene regulation. Using a PCR-based screen, we could identify additional targets of NhhA-dependent gene activation such as the cytokines and growth factors IL-1 alpha, IL-1 beta, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In human monocyte-derived macrophages, G-CSF, GM-CSF, and IL-6 were found to be major targets of NhhA-dependent gene regulation. NhhA induced transcription of IL-6 and G-CSF mRNA via TLR4-dependent pathways, whereas GM-CSF transcription was induced via TLR4-independent pathways. These data provide new insights into the role of NhhA in host-pathogen interaction.

National Category
Immunology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-83022 (URN)10.1128/IAI.00456-12 (DOI)000309971600030 ()
Note

AuthorCount:6;

Available from: 2012-12-05 Created: 2012-12-03 Last updated: 2017-12-07Bibliographically approved
2. Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage of Neisseria meningitidis
Open this publication in new window or tab >>Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage of Neisseria meningitidis
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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.

National Category
Immunology Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-129123 (URN)10.1128/mBio.01670-15 (DOI)000373933100067 ()
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2017-11-30Bibliographically approved
3. CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis
Open this publication in new window or tab >>CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis
(English)Manuscript (preprint) (Other academic)
National Category
Immunology Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-129240 (URN)
Available from: 2016-04-18 Created: 2016-04-18 Last updated: 2016-05-04Bibliographically approved
4. Protective role of CD46 against mycobacterial infection through functional modulation of macrophages
Open this publication in new window or tab >>Protective role of CD46 against mycobacterial infection through functional modulation of macrophages
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology Immunology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-129242 (URN)
Available from: 2016-04-18 Created: 2016-04-18 Last updated: 2016-05-04Bibliographically approved

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