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Bacteria-host cell interactions: Studies on initial colonization, antimicrobial peptides, and biofilms
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The obligate human pathogen Neisseria meningitidis asymptomatically colonizes the upper respiratory tract, but crossing of the epithelial barrier can cause life-threatening meningitis and/or sepsis. N. meningitidis encounters numerous environmental challenges during colonization in the host, and has evolved different evasion strategies and virulence factors to ensure its survival. In contrast, Lactobacillus species are part of the human microbiota and their commensal colonization confers many benefits to the host, including the inhibition of pathogens.

The first cell type encountered by invading bacteria are epithelial cells and immune cells, which can effectively sense and respond to the presence of bacteria by alerting the immune system or by release of antimicrobial peptides. Antimicrobial peptides are small peptides that are able to directly kill bacteria, but also play a role in modulation of immune responses.  

This thesis focuses on the interaction between the human host and bacteria. Paper I shows that epithelial colonization by different bacterial species induces the transcription factor early growth response protein 1 (EGR1). Induction of EGR1 is mediated primarily by signaling through EGFR and ERK1/2 pathway. In paper II the ability of N. meningitidis and Lactobacillus to modulate expression of antimicrobial peptide human beta-defensin 2 (hBD2) in epithelial cells is compared. Expression of hBD2 is upregulated by lactobacilli. In contrast, N. meningitidis dampens this effect, likely mediated by induction of the host molecule A20, a negative regulator of NF-κB. Since N. meningitidis is susceptible to hBD2-mediated killing, exploitation of A20 may be an immune evasion mechanism. In paper III we demonstrate that hBD2 is able to kill N. meningitidis without causing membrane permeabilization. N. meningitidis DNA can bind hBD2 and thereby inhibit hBD2-mediated killing, presenting a possible evasion mechanism. Finally, paper IV shows that the absence of D-lactate dehydrogenase LdhA in N. meningitidis promotes aggregation and biofilm formation through increased autolysis-mediated release of extracellular DNA.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2019. , p. 84
Keywords [en]
Neisseria meningitidis, Lactobacillus, host responses, EGR1, antimicrobial peptides, hBD2, A20, biofilm
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-174761ISBN: 978-91-7797-849-7 (print)ISBN: 978-91-7797-850-3 (electronic)OAI: oai:DiVA.org:su-174761DiVA, id: diva2:1359579
Public defence
2019-11-28, Vivi Täckholm-salen (Q-salen), NPQ-huset, Svante Arrhenius 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 2: Manuscript. Paper 3: Manuscript.

Available from: 2019-11-05 Created: 2019-10-09 Last updated: 2019-10-25Bibliographically approved
List of papers
1. The Host Cell Transcription Factor EGR1 Is Induced by Bacteria through the EGFR-ERK1/2 Pathway
Open this publication in new window or tab >>The Host Cell Transcription Factor EGR1 Is Induced by Bacteria through the EGFR-ERK1/2 Pathway
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2017 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 7, article id 16Article in journal (Refereed) Published
Abstract [en]

The essential first step in bacterial colonization is adhesion to the host epithelial cells. The early host-responses post-bacterial adhesions are still poorly understood. Early growth response 1 (EGR1) is an early response transcriptional regulator that can be rapidly induced by various environmental stimuli. Several bacteria can induce EGR1 expression in host cells, but the involved bacterial characteristics and the underlying molecular mechanisms of this response are largely unknown. Here, we show that EGR1 can be induced in host epithelial cells by different species of bacteria independent of the adherence level, Gram-staining type and pathogenicity. However, bacterial viability and contact with host cells is necessary, indicating that an active interaction between bacteria and the host is important. Furthermore, the strongest response is observed in cells originating from the natural site of the infection, suggesting that the EGR1 induction is cell type specific. Finally, we show that EGFRERK1/2 and beta 1-integrin signaling are the main pathways used for bacteria-mediated EGR1 upregulation. In conclusion, the increase of EGR1 expression in epithelial cells is a common stress induced, cell type specific response upon host-bacteria interaction that is mediated by EGFRERK1/2 and beta 1-integrin signaling.

Keywords
EGR1, bacterial signaling, adhesion, infection, early events, EGFR
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-140313 (URN)10.3389/fcimb.2017.00016 (DOI)000392653300001 ()
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2019-10-10Bibliographically approved
2. Modulation of human beta-defensin 2 expression by pathogenic Neisseria meningitidis and commensal lactobacilli
Open this publication in new window or tab >>Modulation of human beta-defensin 2 expression by pathogenic Neisseria meningitidis and commensal lactobacilli
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-174759 (URN)
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-10-10Bibliographically approved
3. Meningococcal DNA binds to human beta-defensin 2 and blocks its lethal effect against the bacteria
Open this publication in new window or tab >>Meningococcal DNA binds to human beta-defensin 2 and blocks its lethal effect against the bacteria
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(English)Manuscript (preprint) (Other academic)
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-174760 (URN)
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-12-04Bibliographically approved
4. Deletion of D-Lactate Dehydrogenase A in Neisseria meningitidis Promotes Biofilm Formation Through Increased Autolysis and Extracellular DNA Release
Open this publication in new window or tab >>Deletion of D-Lactate Dehydrogenase A in Neisseria meningitidis Promotes Biofilm Formation Through Increased Autolysis and Extracellular DNA Release
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2019 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 422Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is a Gram-negative bacterium that asymptomatically colonizes the human nasopharyngeal mucosa. Pilus-mediated initial adherence of N. meningitidis to the epithelial mucosa is followed by the formation of three-dimensional aggregates, called microcolonies. Dispersal from microcolonies contributes to the transmission of N. meningitidis across the epithelial mucosa. We have recently discovered that environmental concentrations of host cell-derived lactate influences N. meningitidis microcolony dispersal. Here, we examined the ability of N. meningitidis mutants deficient in lactate metabolism to form biofilms. A lactate dehydrogenease A (idhA) mutant had an increased level of biofilm formation. Deletion of IdhA increased the N. meningitidis cell surface hydrophobicity and aggregation. In this study, we used FAM20, which belongs to clonal complex ST-11 that forms biofilms independently of extracellular DNA (eDNA). However, treatment with DNase I abolished the increased biofilm formation and aggregation of the ldhA-delicient mutant, suggesting a critical role for eDNA. Compared to wild-type, the IdhA-deficient mutant exhibited an increased autolytic rate, with significant increases in the eDNA concentrations in the culture supernatants and in biofilms. Within the IdhA mutant biofilm, the transcription levels of the capsule, pilus, and bacterial lysis genes were downregulated, while norB, which is associated with anaerobic respiration, was upregulated. These findings suggest that the absence of IdhA in N. meningitidis promotes biofilm formation and aggregation through autolysis-mediated DNA release.

Keywords
Neisseria meningitidis, lactate dehydrogenase, eDNA, autolysis, biofilm
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-167499 (URN)10.3389/fmicb.2019.00422 (DOI)000460286700001 ()30891026 (PubMedID)
Available from: 2019-04-01 Created: 2019-04-01 Last updated: 2019-10-10Bibliographically approved

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