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Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection
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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2013 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 8, 3704-3712 p.Article in journal (Refereed) Published
Abstract [en]

Meningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action against Neisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activity in vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected with N. meningitidis as well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activity in vivo, indicates the possibility to design peptide-based therapies for infectious diseases.

Place, publisher, year, edition, pages
2013. Vol. 57, no 8, 3704-3712 p.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:su:diva-92792DOI: 10.1128/AAC.00624-13ISI: 000321761800031OAI: oai:DiVA.org:su-92792DiVA: diva2:642782
Note

AuthorCount:7;

Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06Bibliographically approved
In thesis
1. 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
2. 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

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Eriksson, Olaspers SaraGeörg, MiriamSjölinder, HongLindberg, StaffanLangel, ÜloJonsson, Ann-Beth
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