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Loss of Meningococcal PilU Delays Microcolony Formation and Attenuates Virulence In Vivo
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.
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.

Place, publisher, year, edition, pages
2012. Vol. 80, no 7, 2538-2547 p.
National Category
Immunology
Identifiers
URN: urn:nbn:se:su:diva-80040DOI: 10.1128/IAI.06354-11ISI: 000305599400030OAI: oai:DiVA.org:su-80040DiVA: diva2:551953
Note

AuthorCount:3;

Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Pathogenic Neisseria: Single cell motility, multicellular dynamics and antimicrobial susceptibility
Open this publication in new window or tab >>Pathogenic Neisseria: Single cell motility, multicellular dynamics and antimicrobial susceptibility
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neisseria meningitidis and Neisseria gonorrhoeae can colonize humans without causing any symptoms. However, gonorrhea and invasive meningococcal disease are serious health concerns. An essential virulence factor for neisserial adhesion to host cells, twitching motility and microcolony formation/aggregation is the retractile type IV pili (Tfp). The scope of this thesis stretches from the motility of single Neisseria cells, via the multicellular dynamics of N. meningitidis microcolonies, to the bactericidal and endotoxin-inhibiting activity of a novel anti-meningococcal peptide. The Tfp machinery in pathogenic Neisseria is highly conserved. Nevertheless, our data demonstrate species-specific expression levels of the Tfp retraction ATPase PilT. By using live-cell microscopy and particle tracking together with visualization of pili, differences between N. gonorrhoeae and N. meningitidis were also observed in piliation and twitching motility speed. However, these differences could not be attributed to the contrasting PilT expressions per se (Paper I). The importance of PilT for pilus dynamics is well established in the literature while comprehensive knowledge of the paralog PilU is lacking. In Paper II, results suggest that PilU promotes timely formation of microcolonies. Furthermore, both PilU and PilT were required for full virulence of meningococci in vivo. The meningococcal response upon adhesion to host cells includes upregulation of the novel virulence factor Neisseria anti-aggregation factor A (NafA). Our data indicate that NafA limits microcolony formation by preventing excessive formation of Tfp bundles (Paper III). Microcolony dispersal is a prerequisite for close adhesion and mucosal invasion. Dispersal progressed rapidly on host cells and upon induction with host cell-conditioned medium (Paper IV). The dispersal phase was not altered in NafA-deficient meningococci. However, NafA may be important after microcolony dispersal on host cells for maintaining bacteria in a single cell state (Paper IV). In Paper V, a screen of cell-penetrating peptides for antimicrobial activity towards meningococci demonstrated that transportan-10 (TP10) exhibited rapid membrane-disruptive and bactericidal activity. TP10 also decreased bacteraemia levels in a murine model of meningococcal disease. Furthermore, TP10 reduced the proinflammatory effect of endotoxin on macrophages. Thus, TP10 displays two properties that may be utilized for the development of a peptide-based treatment against pathogens.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut, Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 82 p.
Keyword
Neisseria, Type IV pili, Twitching motility, PilT, Microcolony dynamics, PilU, NafA, Antimicrobial peptide, Cell-penetrating peptide
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-108519 (URN)978-91-7649-034-1 (ISBN)
Public defence
2014-12-05, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, 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 1 and 4: Manuscripts.

Available from: 2014-11-13 Created: 2014-10-29 Last updated: 2014-11-21Bibliographically approved
2. 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)
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

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