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Meningococcal resistance to antimicrobial peptides is mediated by bacterial adhesion and host cell RhoA and Cdc42 signalling
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.
2013 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 11, 1938-1954 p.Article in journal (Refereed) Published
Abstract [en]

Antimicrobial peptides (AMPs) constitute an essential part of the innate immune defence. Pathogenic bacteria have evolved numerous strategies to withstand AMP-mediated killing. The influence of host epithelia on bacterial AMP resistance is, however, still largely unknown. We found that adhesion to pharyngeal epithelial cells protected Neisseria meningitidis, a leading cause of meningitis and sepsis, from the human cathelicidin LL-37, the cationic model amphipathic peptide (MAP) and the peptaibol alamethicin, but not from polymyxin B. Adhesion to primary airway epithelia resulted in a similar increase in LL-37 resistance. The inhibition of selective host cell signalling mediated by RhoA and Cdc42 was found to abolish the adhesion-induced LL-37 resistance by a mechanism unrelated to the actin cytoskeleton. Moreover, N. meningitidis triggered the formation of cholesterol-rich membrane microdomains in pharyngeal epithelial cells, and host cell cholesterol proved to be essential for adhesion-induced resistance. Our data highlight the importance of Rho GTPase-dependent host cell signalling for meningococcal AMP resistance. These results indicate that N. meningitidis selectively exploits the epithelial microenvironment in order to protect itself from LL-37.

Place, publisher, year, edition, pages
2013. Vol. 15, no 11, 1938-1954 p.
National Category
Microbiology Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-92688DOI: 10.1111/cmi.12163ISI: 000325541700012OAI: oai:DiVA.org:su-92688DiVA: diva2:640888
Note

AuthorCount: 4;

Available from: 2013-08-14 Created: 2013-08-14 Last updated: 2017-10-24Bibliographically approved
In thesis
1. Interplay between bacteria and host epithelial cells
Open this publication in new window or tab >>Interplay between bacteria and host epithelial cells
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bacterial pathogens have developed multiple ways of manipulating host cell functions to exploit the host environment. We found that interactions with epithelial cells increase the resistance of the human pathogen Neisseria meningitidis to the antimicrobial peptide LL-37. This resistance was dependent on host cell cholesterol-rich microdomains and RhoA/Cdc42-dependent signalling.

At mucosal surfaces, pathogenic bacteria compete with the resident microbiota. Lactobacillus inhibits the adherence of a wide range of pathogens, however, the mechanisms of inhibition are still largely unknown. We demonstrate that certain lactobacilli interfere with host cell signalling pathways used by pathogenic bacteria during initial colonisation. Inhibitory lactobacilli blocked the pathogen-induced activation of Src, increases of host cytosolic [Ca2+] and upregulation of Egr1, in a TLR2-dependent fashion. We further identify Egr1 as a host factor crucial for efficient pathogen adherence. The pathogens used in these studies were N. meningitidis, Helicobacter pylori and Streptococcus pyogenes.

In summary, these studies highlight that the interplay between bacteria and host cells is a critical determinant of pathogenesis and bacterial co-existence in the host.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 96 p.
Keyword
Microbial-cell interaction, Adherence, Infection, Lactic acid bacteria, Antimicrobial peptides
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-92692 (URN)978-91-7447-735-1 (ISBN)
Public defence
2013-09-20, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Epub ahead of print. Paper 3: Submitted. Paper 4: Manuscript.

Available from: 2013-08-29 Created: 2013-08-14 Last updated: 2013-08-19Bibliographically approved
2. Antimicrobial peptides and virulence factors in meningococcal colonisation and disease
Open this publication in new window or tab >>Antimicrobial peptides and virulence factors in meningococcal colonisation and disease
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Gram-negative bacterium Neisseria meningitidis is a transient commensal of the human nasopharynx, but occasionally causes life-threatening disease. During colonisation of its niche, N. meningitidis has to overcome innate immune defences, including the expression of antimicrobial peptides (AMPs). Meningococcal resistance to the host defence peptide LL-37 was investigated in Papers I and II. The polysaccharide capsule and lipopolysaccharide (LPS) were found to increase LL-37 resistance by inhibiting peptide binding to the bacteria. Further, N. meningitidis responded to sub-lethal doses of LL-37 by an increase in capsule biosynthesis. Intriguingly, adhesion to epithelial cells and tissues protected N. meningitidis from physiological concentrations of LL-37 and two other helical peptides. The protective effect was mediated by RhoA- and Cdc42-dependent host cell signalling and cholesterol-rich membrane microdomains. The host epithelium thus seems to play an active role in AMP resistance.

Cell-penetrating peptides (CPPs) are structurally related to AMPs, but are primarily employed for the delivery of membrane-impermeable molecules in vitro and in vivo. In Paper III, several of these peptides were screened for antimicrobial activity against N. meningitidis. The best candidate, transportan-10 (TP10), exhibited membrane-disruptive, bactericidal activity and decreased bacteraemia levels in a mouse model of meningococcal disease. Additionally, TP10 inhibited binding of LPS to macrophages, thereby neutralising its inflammatory effect. These dual effects of TP10 may potentially be harnessed for the treatment of invasive disease.

The role of the N. meningitidis polynucleotide phosphorylase (PNPase) homologue in pathogenesis was studied in Paper IV. PNPase-deficient meningococci were hyper-aggregative and resistant to normal human serum, and these phenotypes were associated with an accumulation of extracellular DNA on the pili and surface of the bacteria. Wild-type meningococci differentially regulated PNPase expression in contact with epithelial cells and in human serum, suggesting the dynamic regulation of PNPase levels during pathogenesis.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2014. 68 p.
Keyword
Neisseria meningitidis, antimicrobial peptide, LL-37, cell-penetrating peptide, resistance, polynucleotide phosphorylase
National Category
Microbiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-99175 (URN)978-91-7447-849-5 (ISBN)
Public defence
2014-02-21, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, 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: 2014-01-30 Created: 2014-01-12 Last updated: 2014-01-22Bibliographically approved

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