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Meningococcal outer membrane protein NhhA is essential for colonization and disease by preventing phagocytosis and complement attack
Uppsala University. (Ann-Beth Jonsson)
Uppsala University. (Ann-Beth Jonsson)
Uppsala University. (Ann-Beth Jonsson)
Uppsala University. (Ann-Beth Jonsson)
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2008 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 11, 5412-5420 p.Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is a leading cause of meningitis and septicemia worldwide, with a rapid onset of disease and a high morbidity and mortality. NhhA is a meningococcal outer membrane protein included in the family of trimeric autotransporter adhesins. The protein binds to the extracellular matrix proteins heparan sulfate and laminin and facilitates attachment to host epithelial cells. In this study, we show that NhhA is essential for bacterial colonization of the nasopharyngeal mucosa in a murine model of meningococcal disease. Successful colonization depends on bacterial attachment but also to the capacity to overcome innate host immune responses. We found that NhhA protected bacteria from phagocytosis, which is important for the mucosal survival of bacteria. In addition, NhhA mediated extensive serum resistance that increased bacterial survival in blood and promoted lethal sepsis. The presence of NhhA protected bacteria from complement-mediated killing by preventing the deposition of the membrane attack complex. Taken together, the results of this work reveal that NhhA inhibits phagocytosis and protects bacteria against complement-mediated killing, which enhances both nasal colonization and the development of sepsis in vivo.

Place, publisher, year, edition, pages
2008. Vol. 76, no 11, 5412-5420 p.
Keyword [en]
NhhA, Host-pathogen interactions, Neisseria
National Category
Microbiology
Research subject
Molecular Immunology; Molecular Biology; Microbiology
Identifiers
URN: urn:nbn:se:su:diva-65800DOI: 10.1128/IAI.00478-08OAI: oai:DiVA.org:su-65800DiVA: diva2:464829
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Virulence Factors and Motility Mechanisms of Pathogenic Neisseria
Open this publication in new window or tab >>Virulence Factors and Motility Mechanisms of Pathogenic Neisseria
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neisseria gonorrhoeae and Neisseria meningitidis are two closely related human specific pathogens. Neisseria gonorrhoeae is the causative agent for the sexually transmitted disease gonorrhea and often causes asymptomatic infections in women which is a cause of infertility. Neisseria meningitidis is a major cause of mortality world-wide through bacterial meningitis and septicemia. The severity of meningococcal disease, especially in sub-Saharan Africa warrants development of effective vaccines against serogroups that currently lack them. Here, Neisseria host-pathogen interactions and common virulence factors that may prove useful in vaccine development and in understanding disease caused by pathogenic Neisseria are reviewed and investigated. The aim of this thesis is to investigate the virulence-associated properties of the universally expressed N. meningitidis proteins NhhA, NafA, PilU and PilT, as well as to characterize the twitching motility of the pathogenic Neisseria. The conserved autotransporter adhesin NhhA has in Paper I of this thesis been investigated in a murine model of meningococcemia and found to be important for intranasal colonization and disease outcome of N. meningitidis in CD46 transgenic mice. NafA has in Paper II of this thesis been named and identified as a novel anti-aggregation factor that impacts both pilus bundling and the virulence potential of N. meningitidis. The ATPases, PilU and PilT, which are involved in the functionality of pili were studied in Paper III of this thesis. PilU and PilT were found to modulate Neisseria microcolony formation, host cell adhesion, pilus retraction, serum resistance, as well as mortality in a mouse model of meningococcal disease. Finally, Paper IV of this thesis also provides novel insights into the nature of twitching motility in pathogenic Neisseria. By live-cell microscopy and automated particle tracking coupled with visualization of pili in motile bacteria we found that N. meningitidis strains, on average, move faster and utilizes more pili then N. gonorrhoeae. In summary, this thesis investigates Neisseria virulence factors in general, type IV pili in particular and characterizes the roles of several virulence-associated proteins and twitching motility in the pathogenic Neisseria.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2012. 61 p.
Keyword
Neisseria, Virulence factors, Type IV pili, PilT, PilU, NafA, NhhA, Twitching motility
National Category
Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-65812 (URN)978-91-7447-423-7 (ISBN)
Public defence
2012-01-27, sal G, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 13:00 (English)
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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: 2012-01-04 Created: 2011-12-14 Last updated: 2014-10-31Bibliographically approved

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