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Host cell-derived lactate functions as an effector molecule in Neisseria meningitidis microcolony dispersal
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 82017 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, no 4, article id e1006251Article in journal (Refereed) Published
Abstract [en]

The development of meningococcal disease, caused by the human pathogen Neisseria meningitidis, is preceded by the colonization of the epithelial layer in the nasopharynx. After initial adhesion to host cells meningococci form aggregates, through pilus-pilus interactions, termed microcolonies from which the bacteria later detach. Dispersal from microcolonies enables access to new colonization sites and facilitates the crossing of the cell barrier; however, this process is poorly understood. In this study, we used live-cell imaging to investigate the process of N. meningitidis microcolony dispersal. We show that direct contact with host cells is not required for microcolony dispersal, instead accumulation of a host-derived effector molecule induces microcolony dispersal. By using a host-cell free approach, we demonstrated that lactate, secreted from host cells, initiate rapid dispersal of microcolonies. Interestingly, metabolic utilization of lactate by the bacteria was not required for induction of dispersal, suggesting that lactate plays a role as a signaling molecule. Furthermore, Neisseria gonorrhoeae microcolony dispersal could also be induced by lactate. These findings reveal a role of host-secreted lactate in microcolony dispersal and virulence of pathogenic Neisseria.

Place, publisher, year, edition, pages
2017. Vol. 13, no 4, article id e1006251
National Category
Biological Sciences Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-144725DOI: 10.1371/journal.ppat.1006251ISI: 000402555700005OAI: oai:DiVA.org:su-144725DiVA, id: diva2:1127916
Available from: 2017-07-20 Created: 2017-07-20 Last updated: 2018-11-02Bibliographically approved
In thesis
1. Influence of host and bacterial factors during Neisseria meningitidis colonization
Open this publication in new window or tab >>Influence of host and bacterial factors during Neisseria meningitidis colonization
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human-restricted pathogen Neisseria meningitidis is a major cause of bacterial meningitis and sepsis worldwide. Colonization of the mucosal layer in the upper respiratory tract is essential to establish an asymptomatic carrier state and invasive disease. N. meningitidis encounters diverse environmental challenges during colonization and has evolved multiple strategies and virulence factors to survive and adapt within the host.

Upon initial adhesion to the host epithelial cells, N. meningitidis forms pilus-mediated aggregates called microcolonies, which are characterized by interbacterial and host-cell interactions. Microcolonies promote long-term asymptomatic colonization within the host. However, the dispersal of single bacteria from microcolonies can help N. meningitidis to develop close contact with host cells and facilitate the invasion of mucosal surfaces or transmission to a new host.

This thesis focuses on understanding how the interplay between the host, environment, and virulence factors influences N. meningitidis colonization. Paper I shows that the host-derived metabolite lactate induces rapid dispersal of N. meningitidis microcolonies. Further molecular characterization in Paper II revealed that lactate-induced dispersal is mediated by pilus retraction, occurs in a density-dependent manner, and is responsive to temperature. Paper III shows that the deletion of D-lactate dehydrogenase LdhA in N. meningitidis promotes aggregation and biofilm formation through an increase in the autolysis-mediated release of extracellular DNA. Finally, Paper IV examines the role of polynucleotide phosphorylase (PNPase) in the virulence of N. meningitidis. The deletion of PNPase resulted in a pilus-dependent increase in the aggregation and adhesion to epithelial cells. A PNPase mutant was growth deficient and highly attenuated in an in vivo mouse model. Transcriptional analysis revealed that PNPase plays a role as a major regulator in N. meningitidis.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2018. p. 75
Keywords
Neisseria meningitidis, Colonization, Host-bacteria interactions, Lactate, Biofilms, Polynucleotide phosphorylase
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-161566 (URN)978-91-7797-474-1 (ISBN)978-91-7797-475-8 (ISBN)
Public defence
2018-12-18, Vivi Täckholm-salen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 10:00 (English)
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Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

Available from: 2018-11-23 Created: 2018-10-31 Last updated: 2018-11-16Bibliographically approved

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Sigurlásdóttir, SaraSaroj, Sunil D.Zguna, NadezdaIlag, Leopold L.Jonsson, Ann-Beth
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