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Host-bacteria interactions: Host cell responses and bacterial pathogenesis
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Helicobacter pylori colonizes the human stomach, where it causes gastritis that may develop into peptic ulcer disease or cancer when left untreated. Neisseria gonorrhoeae colonizes the urogenital tract and causes the sexually transmitted disease gonorrhea. In contrast, Lactobacillus species are part of the human microbiota, which is the resident microbial community, and are considered to be beneficial for health. The first host cell types that bacteria encounter when they enter the body are epithelial cells, which form the border between the inside and the outside, and macrophages, which are immune cells that engulf unwanted material.      

The focus of this thesis has been the interaction between the host and bacteria, aiming to increase our knowledge of the molecular mechanisms that underlie the host responses and their effects on bacterial pathogenicity. Understanding the interactions between bacteria and the host will hopefully enable the development of new strategies for the treatment of infectious disease.

In paper I, we investigated the effect of N. gonorrhoeae on the growth factor amphiregulin in cervical epithelial cells and found that the processing and release of amphiregulin changes upon infection. In paper II, we examined the expression of the transcription factor early growth response-1 (EGR1) in epithelial cells during bacterial colonization. We demonstrated that EGR1 is rapidly upregulated by many different bacteria. This upregulation is independent of the pathogenicity, Gram-staining type and level of adherence of the bacteria, but generally requires viable bacteria and contact with the host cell. The induction of EGR1 is mediated primarily by signaling through EGFR, ERK1/2 and β1-integrins. In paper III, we described the interactions of the uncharacterized protein JHP0290, which is secreted by H. pylori, with host cells. JHP0290 is able to bind to several cell types and induces apoptosis and TNF release in macrophages. For both of these responses, signaling through Src family kinases and ERK is essential. Apoptosis is partially mediated by TNF release. Finally, in paper IV, we showed that certain Lactobacillus strains can reduce the colonization of H. pylori on gastric epithelial cells. Lactobacilli decrease the gene expression of SabA and thereby inhibit the binding mediated by this adhesin.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2016. , 42 p.
Keyword [en]
Host-bacteria interaction, Helicobacter pylori, Neisseria gonorrhoeae, Lactobacillus, Epithelial cells, Macrophages, EGR1, Amphiregulin, SabA
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-126425ISBN: 978-91-7649-331-1 (print)OAI: oai:DiVA.org:su-126425DiVA: diva2:900576
Public defence
2016-03-18, Vivi Täckholmsalen (Q-salen) NPQ-huset, Svante Arrhenius väg 20, Stockholm, 13:00 (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 4: Manuscript.

Available from: 2016-02-24 Created: 2016-02-01 Last updated: 2017-02-17Bibliographically approved
List of papers
1. Neisseria gonorrhoeae Infection Induces Altered Amphiregulin Processing and Release
Open this publication in new window or tab >>Neisseria gonorrhoeae Infection Induces Altered Amphiregulin Processing and Release
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, e16369Article in journal (Refereed) Published
Abstract [en]

Adhesion of the human pathogen Neisseria gonorrhoeae has established effects on the host cell and evokes a variety of cellular events including growth factor activation. In the present study we report that infection with N. gonorrhoeae causes altered amphiregulin processing and release in human epithelial cells. Amphiregulin is a well-studied growth factor with functions in various cell processes and is upregulated in different forms cancer and proliferative diseases. The protein is prototypically cleaved on the cell surface in response to external stimuli. We demonstrate that upon infection, a massive upregulation of amphiregulin mRNA is seen. The protein changes its subcellular distribution and is also alternatively cleaved at the plasma membrane, which results in augmented release of an infection-specific 36 kDa amphiregulin product from the surface of human cervical epithelial cells. Further, using antibodies directed against different domains of the protein we could determine the impact of infection on pro-peptide processing. In summary, we present data showing that the infection of N. gonorrhoeae causes an alternative amphiregulin processing, subcellular distribution and release in human epithelial cervical cells that likely contribute to the predisposition cellular abnormalities and anti-apoptotic features of N. gonorrhoeae infections. 

National Category
Biological Sciences Cell and Molecular Biology
Research subject
Microbiology; Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-63651 (URN)10.1371/journal.pone.0016369 (DOI)000286663900042 ()
Available from: 2011-10-26 Created: 2011-10-26 Last updated: 2017-12-08Bibliographically approved
2. 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
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-126423 (URN)
Available from: 2016-02-01 Created: 2016-02-01 Last updated: 2016-02-05Bibliographically approved
3. Helicobacter pylori Protein JHP0290 Binds to Multiple Cell Types and Induces Macrophage Apoptosis via Tumor Necrosis Factor (TNF)-Dependent and Independent Pathways
Open this publication in new window or tab >>Helicobacter pylori Protein JHP0290 Binds to Multiple Cell Types and Induces Macrophage Apoptosis via Tumor Necrosis Factor (TNF)-Dependent and Independent Pathways
Show others...
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, e77872Article in journal (Refereed) Published
Abstract [en]

Activated macrophages at the sub-mucosal space play a major role in generating innate immune responses during H. pylori infection. Final disease outcome largely depends on how H. pylori and bacterium-derived products modulate macrophage responses. Here, we report that JHP0290, a functionally unknown protein from H. pylori, regulates macrophage functions. Recombinant purified JHP0290 (rJHP0290) had the ability to bind to several cell types including macrophages, human gastric epithelial cell lines, human monocyte-derived dendritic cells (MoDC) and human neutrophils. Exposure to rJHP0290 induced apoptosis in macrophages concurrent with release of proinflammatory cytokine tumor necrosis factor (TNF). A mutant strain of H. pylori disrupted in the jhp0290 gene was significantly impaired in its ability to induce apoptosis and TNF in macrophages confirming the role of endogenous protein in regulating macrophage responses. Intracellular signaling involving Src family of tyrosine kinases (SFKs) and ERK MAPK were required for rJHP0290-induced TNF release and apoptosis in macrophages. Furthermore, rJHP0290-induced TNF release was partly dependent on activation of nuclear transcription factor-kappa B (NF-kappa B). Neutralizing antibodies against TNF partially blocked rJHP0290-induced macrophage apoptosis indicating TNF-independent pathways were also involved. These results provide mechanistic insight into the potential role of the protein JHP0290 during H. pylori-associated disease development. By virtue of its ability to induce TNF, an acid suppressive proinflammatory cytokine and induction of macrophage apoptosis, JHP0290 possibly helps in persistent survival of the bacterium inside the stomach.

National Category
Biological Sciences Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-97395 (URN)10.1371/journal.pone.0077872 (DOI)000326499300012 ()
Funder
Swedish Research CouncilSwedish Cancer Society
Note

AuthorCount:5;

Available from: 2013-12-11 Created: 2013-12-09 Last updated: 2017-12-06Bibliographically approved
4. Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression
Open this publication in new window or tab >>Lactobacilli Reduce Helicobacter pylori Attachment to Host Gastric Epithelial Cells by Inhibiting Adhesion Gene Expression
Show others...
2016 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 84, no 5, 1526-1535 p.Article in journal (Refereed) Published
Abstract [en]

The human gastrointestinal tract, including the harsh environment of the stomach, harbors a large variety of bacteria, of which Lactobacillus species are prominent members. The molecular mechanisms by which species of lactobacilli interfere with pathogen colonization are not fully characterized. In this study, we aimed to study the effect of lactobacillus strains upon the initial attachment of Helicobacter pylori to host cells. Here we report a novel mechanism by which lactobacilli inhibit adherence of the gastric pathogen H. pylori. In a screen with Lactobacillus isolates, we found that only a few could reduce adherence of H. pylori to gastric epithelial cells. Decreased attachment was not due to competition for space or to lactobacillus-mediated killing of the pathogen. Instead, we show that lactobacilli act on H. pylori directly by an effector molecule that is released into the medium. This effector molecule acts on H. pylori by inhibiting expression of the adhesin-encoding gene sabA. Finally, we verified that inhibitory lactobacilli reduced H. pylori colonization in an in vivo model. In conclusion, certain Lactobacillus strains affect pathogen adherence by inhibiting sabA expression and thereby reducing H. pylori binding capacity.

National Category
Biochemistry and Molecular Biology Microbiology in the medical area
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-132000 (URN)10.1128/IAI.00163-16 (DOI)000377106600026 ()26930708 (PubMedID)
Available from: 2016-08-12 Created: 2016-07-05 Last updated: 2017-11-28Bibliographically approved

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