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  • 1.
    Eriksson, Olaspers Sara
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Geörg, Miriam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sillard, Rannar
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lindberg, Staffan
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Identification of Cell-Penetrating Peptides That Are Bactericidal to Neisseria meningitidis and Prevent Inflammatory Responses upon Infection2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 8, p. 3704-3712Article in journal (Refereed)
    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.

  • 2.
    Geörg, Miriam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Antimicrobial peptides and virulence factors in meningococcal colonisation and disease2014Doctoral 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.

  • 3.
    Geörg, Miriam
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Maudsdotter, Lisa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Tavares, Raquel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Meningococcal resistance to antimicrobial peptides is mediated by bacterial adhesion and host cell RhoA and Cdc42 signalling2013In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 11, p. 1938-1954Article in journal (Refereed)
    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.

  • 4. Jones, Allison
    et al.
    Geörg, Miriam
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Uppsala universitet.
    Maudsdotter, Lisa
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Uppsala universitet.
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology. Uppsala universitet.
    Endotoxin, capsule, and bacterial attachment contribute to Neisseria meningitidis resistance to the human antimicrobial peptide LL-372009In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 191, no 12, p. 3861-3868Article in journal (Refereed)
    Abstract [en]

    Pathogenic bacteria have evolved numerous mechanisms to evade the human immune system and have developed widespread resistance to traditional antibiotics. We studied the human pathogen Neisseria meningitidis and present evidence of novel mechanisms of resistance to the human antimicrobial peptide LL-37. We found that bacteria attached to host epithelial cells are resistant to 10 microM LL-37 whereas bacteria in solution or attached to plastic are killed, indicating that the cell microenvironment protects bacteria. The bacterial endotoxin lipooligosaccharide and the polysaccharide capsule contribute to LL-37 resistance, probably by preventing LL-37 from reaching the bacterial membrane, as more LL-37 reaches the bacterial membrane on both lipooligosaccharide-deficient and capsule-deficient mutants whereas both mutants are also more susceptible to LL-37 killing than the wild-type strain. N. meningitidis bacteria respond to sublethal doses of LL-37 and upregulate two of their capsule genes, siaC and siaD, which further results in upregulation of capsule biosynthesis.

  • 5. Khairalla, Ahmed S.
    et al.
    Omer, Sherko A.
    Mahdavi, Jafar
    Aslam, Akhmed
    Dufailu, Osman A.
    Self, Tim
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Geörg, Miriam
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sjölinder, Hong
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Royer, Pierre-Joseph
    Martinez-Pomares, Luisa
    Ghaemmaghami, Amir M.
    Wooldridge, Karl G.
    Oldfield, Neil J.
    Ala'Aldeen, Dlawer A. A.
    Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal App and MspA autotransporters2015In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 17, no 7, p. 1008-1020Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.

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