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Virulence Factors and Motility Mechanisms of Pathogenic Neisseria
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. (Ann-Beth Jonsson)
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 [en]
Neisseria, Virulence factors, Type IV pili, PilT, PilU, NafA, NhhA, Twitching motility
National Category
Microbiology
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-65812ISBN: 978-91-7447-423-7 (print)OAI: oai:DiVA.org:su-65812DiVA: diva2:464886
Public defence
2012-01-27, sal 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: 2012-01-04 Created: 2011-12-14 Last updated: 2014-10-31Bibliographically approved
List of papers
1. Meningococcal outer membrane protein NhhA is essential for colonization and disease by preventing phagocytosis and complement attack
Open this publication in new window or tab >>Meningococcal outer membrane protein NhhA is essential for colonization and disease by preventing phagocytosis and complement attack
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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.

Keyword
NhhA, Host-pathogen interactions, Neisseria
National Category
Microbiology
Research subject
Molecular Immunology; Molecular Biology; Microbiology
Identifiers
urn:nbn:se:su:diva-65800 (URN)10.1128/IAI.00478-08 (DOI)
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2017-12-08Bibliographically approved
2. NafA negatively controls Neisseria meningitidis piliation
Open this publication in new window or tab >>NafA negatively controls Neisseria meningitidis piliation
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, e21749- p.Article in journal (Refereed) Published
Abstract [en]

Bacterial auto-aggregation is a critical step during adhesion of N. meningitidis to host cells. The precise mechanisms and functions of bacterial auto-aggregation still remain to be fully elucidated. In this work, we characterize the role of a meningococcal hypothetical protein, NMB0995/NMC0982, and show that this protein, here denoted NafA, acts as an anti-aggregation factor. NafA was confirmed to be surface exposed and was found to be induced at a late stage of bacterial adherence to epithelial cells. A NafA deficient mutant was hyperpiliated and formed bundles of pili. Further, the mutant displayed increased adherence to epithelial cells when compared to the wild-type strain. In the absence of host cells, the NafA deficient mutant was more aggregative than the wild-type strain. The in vivo role of NafA in sepsis was studied in a murine model of meningococcal disease. Challenge with the NafA deficient mutant resulted in lower bacteremia levels and mortality when compared to the wild-type strain. The present study reveals that meningococcal NafA is an anti-aggregation factor with strong impact on the disease outcome. These data also suggest that appropriate bacterial auto-aggregation is controlled by both aggregation and anti-aggregation factors during Neisseria infection in vivo.

National Category
Microbiology
Identifiers
urn:nbn:se:su:diva-63671 (URN)10.1371/journal.pone.0021749 (DOI)000292293400029 ()21747953 (PubMedID)
Available from: 2011-10-26 Created: 2011-10-26 Last updated: 2017-12-08Bibliographically approved
3. Difference in twitching motility between Neisseria meningitidis and Neisseria gonorrhoeae and its relation to pilus dynamics
Open this publication in new window or tab >>Difference in twitching motility between Neisseria meningitidis and Neisseria gonorrhoeae and its relation to pilus dynamics
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Type IV pili of pathogenic Neisseria, i. e. Neisseria gonorrhoeae and Neisseria meningitidis, are essential for initial attachment to host cells, induction of signal transduction cascades and disease development. A characteristic feature of type IV pili is their ability to retract, which generates forces that move bacteria over surfaces. However, the relation between bacterial motility and pilus dynamics remains poorly understood. In this work we analyzed bacterial motility and monitored movement of fluorescently labeled pili by live cell imaging. We found that movement of N. meningitidis occurred at higher speed and with a larger number of retracting pili than for N. gonorrhoeae. Analysis of time-lapse images suggested that N. gonorrhoeae most often moved using one retracting pilus, whereas N. meningitidis most often used four pili. There were no differences in the membrane distribution of PilT among strains. However, we found significantly higher levels of PilT in N. gonorrhoeae than in N. meningitidis. This produces a higher retraction probability, which could contribute to explaining the lower number of pili observed in N. gonorrhoeae. Finally, we propose a mechanism for how the speed of bacterial movement on a surface depends on the number of retracting pili.

Keyword
Type IV pili, twitching motility, PilT, Neisseria
National Category
Microbiology
Research subject
Biophysics; Microbiology
Identifiers
urn:nbn:se:su:diva-65804 (URN)
Available from: 2011-12-14 Created: 2011-12-14 Last updated: 2011-12-14Bibliographically approved
4. Loss of Meningococcal PilU Delays Microcolony Formation and Attenuates Virulence In Vivo
Open this publication in new window or tab >>Loss of Meningococcal PilU Delays Microcolony Formation and Attenuates Virulence In Vivo
2012 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 80, no 7, 2538-2547 p.Article in journal (Refereed) Published
Abstract [en]

Neisseria meningitidis is a major cause of sepsis and bacterial meningitis worldwide. This bacterium expresses type IV pili (Tfp), which mediate important virulence traits such as the formation of bacterial aggregates, host cell adhesion, twitching motility, and DNA uptake. The meningococcal PilT protein is a hexameric ATPase that mediates pilus retraction. The PilU protein is produced from the pilT-pilU operon and shares a high degree of homology with PilT. The function of PilT in Tfp biology has been studied extensively, whereas the role of PilU remains poorly understood. Here we show that pilU mutants have delayed microcolony formation on host epithelial cells compared to the wild type, indicating that bacterium-bacterium interactions are affected. In normal human serum, the pilU mutant survived at a higher rate than that for wild-type bacteria. However, in a murine model of disease, mice infected with the pilT mutant demonstrated significantly reduced bacterial blood counts and survived at a higher rate than that for mice infected with the wild type. Infection of mice with the pilU mutant resulted in a trend of lower bacteremia, and still a significant increase in survival, than that of the wild type. In conclusion, these data suggest that PilU promotes timely microcolony formation and that both PilU and PilT are required for full bacterial virulence.

National Category
Immunology
Identifiers
urn:nbn:se:su:diva-80040 (URN)10.1128/IAI.06354-11 (DOI)000305599400030 ()
Note

AuthorCount:3;

Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved

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