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Pathogenic Neisseria Hitchhike on the Uropod of Human Neutrophils
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, e24353- p.Article in journal (Refereed) Published
Abstract [en]

Polymorphonuclear neutrophils (PMNs) are important components of the human innate immune system and are rapidly recruited at the site of bacterial infection. Despite the effective phagocytic activity of PMNs, Neisseria gonorrhoeae infections are characterized by high survival within PMNs. We reveal a novel type IV pilus-mediated adherence of pathogenic Neisseria to the uropod (the rear) of polarized PMNs. The direct pilus-uropod interaction was visualized by scanning electron microscopy and total internal reflection fluorescence (TIRF) microscopy. We showed that N. meningitidis adhesion to the PMN uropod depended on both pilus-associated proteins PilC1 and PilC2, while N. gonorrhoeae adhesion did not. Bacterial adhesion elicited accumulation of the complement regulator CD46, but not I-domain-containing integrins, beneath the adherent bacterial microcolony. Electrographs and live-cell imaging of PMNs suggested that bacterial adherence to the uropod is followed by internalization into PMNs via the uropod. We also present data showing that pathogenic Neisseria can hitchhike on PMNs to hide from their phagocytic activity as well as to facilitate the spread of the pathogen through the epithelial cell layer. 

Place, publisher, year, edition, pages
2011. Vol. 6, no 9, e24353- p.
National Category
Microbiology
Research subject
Microbiology; Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-63644DOI: 10.1371/journal.pone.0024353ISI: 000295173800021OAI: oai:DiVA.org:su-63644DiVA: diva2:451600
Available from: 2011-10-26 Created: 2011-10-26 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Neisseria gonorrhoeae and Lactobacillus from initial adherence to effects on human cells
Open this publication in new window or tab >>Neisseria gonorrhoeae and Lactobacillus from initial adherence to effects on human cells
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The causative agent of gonorrhoea Neisseria gonorrhoeae (gonococcus) colonises the urogenital tract epithelia. The vaginal tract microbiota of healthy females is dominated by Lactobacillus species. In paper I, the ability of lactobacilli to protect cervical cells against gonococcal adherence was investigated. The number of adhered lactobacilli did not correlate to the level of protection against gonococci. Instead, the protection was dependent on specific Lactobacillus isolates. Gonococci able to outmanoeuvre the normal microbiota colonise and may elicit an influx of neutrophils. In paper II the initial interaction between pathogens and neutrophils was investigated. N. gonorrhoeae was found to bind to the non-phagocytic rear (uropod) of the neutrophils. Results suggest that uropod binding is a trait specific of Neisseria species. By binding to the uropod bacteria could avoid the phagocytic front part of the neutrophils whilst being transported across the epithelial cell layer to new sites. Since gonorrhoea has been associated with cancer in several studies, effects of gonococcal colonisation on eukaryote genome integrity was investigated in paper III.  N. gonorrhoeae caused DNA stand breaks in vaginal epithelial cells and decreased the level of tumor protein p53. Infected cells showed increase of cyclin-dependent kinase inhibitors p21 and p27 along with reduced proliferation. The impact of lactobacilli colonisation on cervical cell proliferation was investigated in paper IV. Three out of four Lactobacillus isolates tested reduced cell proliferation. Decreased pH due to lactic acid production was found to be a contributing factor. However, vaginal isolated L. gasseri required a direct bacteria-cell interaction to affect cell cycle progression. Additional unknown factors also contributed as in the case of saliva isolated L. reuteri. In summary, this thesis investigates N. gonorrhoeae pathogenesis and the impact of Lactobacillus species in protection and colonisation.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2012. 54 p.
Keyword
Neisseria gonorrhoeae, Lactobacillus, adhesion, cell cycle, DNA damage, Neutrophils
National Category
Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-75490 (URN)978-91-7447-522-7 (ISBN)
Public defence
2012-05-25, lecture room G, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, 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 3: Manuscript. Paper 4: Manuscript.

Available from: 2012-05-03 Created: 2012-04-20 Last updated: 2014-09-29Bibliographically approved
2. Pathogenic Neisseria infections of human neutrophils and epithelial cells: focusing on host responses and immune evasion
Open this publication in new window or tab >>Pathogenic Neisseria infections of human neutrophils and epithelial cells: focusing on host responses and immune evasion
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

N. meningitidis and N. gonorrhoeae are obligate human pathogens that colonize mucosal surfaces and are often carried asymptomatically. These bacteria have developed adhesive structures that promote adherence to host cells and efficient colonization of new hosts. N. gonorrhoeae causes the sexually transmitted disease gonorrhea, which remains one of the most common sexually transmitted diseases, despite the availability of effective antibiotic treatments. N. meningitidis is frequently found in the nasopharynx of healthy individuals as a part of the normal microbiota. However, this bacterial species is a major cause of mortality when it causes septicemia and epidemic meningitidis. The design of vaccines conferring protection against multiple serogroups is difficult; this fact, combined with increased global resistance to antibiotics, emphasizes the need for a better understanding of the pathogenesis of these species. The aim of this thesis was to study the effects of bacterial adherence to human neutrophils (PMNs) and epithelial cells. The adherence of N. meningitidis and N. gonorrhoeae to primary PMNs was investigated in Paper I. Specific adherence of the bacteria to the PMN uropod was observed. By adhering to the uropod, the bacteria could avoid phagocytosis and use the migrating PMNs for transportation. The type IV pilus, which is a known bacterial adhesin, was found to promote uropod adherence. In Paper II, adherence of N. gonorrhoeae to non-polarized cervical and vaginal epithelial cells was found to cause DNA damage and delay cell cycle progression. Upregulation and nuclear localization of the cyclin-dependent kinase inhibitors p21 and p27 were observed, which could contribute to reduced cell proliferation. Interestingly, the levels of tumor suppressing protein 53 (TP53) were affected by bacterial colonization in a non-tumor cell line. In Paper III, colonization by Lactobacillus spp. was found to induce the accumulation of host cells in G1 phase and the upregulation of p21. The adherence of N. gonorrhoeae to polarized epithelial cells and the impact of PMN presence were investigated in Paper IV. N. gonorrhoeae adherence to polarized epithelial cells was significantly higher than adherence to non polarized cells. Cell culture medium containing degranulated products from stimulated PMNs was found to promote bacterial adherence. Finally, PMNs with bacteria adhered to the uropod were able to transport the bacteria through a polarized cell layer. In summary, this thesis investigates the impact of adhesion of pathogenic Neisseria spp. to host epithelial cells and PMNs. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 59 p.
Keyword
Neisseria meningitidis, Neisseria gonorrhoeae, Neutrophils, PMN, Epithelial cells, Polarized cells, Type IV pili, Adherence, Cell cycle, DNA damage, Lactobacillus
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-92446 (URN)978-91-7447-725-2 (ISBN)
Public defence
2013-09-06, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

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

Available from: 2013-08-15 Created: 2013-08-05 Last updated: 2013-08-13Bibliographically approved

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