TY - JOUR A1 - Firdessa, Rebuma A1 - Good, Liam A1 - Amstalden, Maria Cecilia A1 - Chindera, Kantaraja A1 - Kamaruzzaman, Nor Fadhilah A1 - Schultheis, Martina A1 - Röger, Bianca A1 - Hecht, Nina A1 - Oelschlaeger, Tobias A. A1 - Meinel, Lorenz A1 - Lühmann, Tessa A1 - Moll, Heidrun T1 - Pathogen- and host-directed antileishmanial effects mediated by polyhexanide (PHMB) JF - PLoS Neglected Tropical Diseases N2 - Background Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. Methodology/Principal Findings Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. Conclusions Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators. KW - resistance KW - activation KW - dendritic cells KW - Cutaneous leishmaniasis KW - topical treatment KW - biocide polyhexamethylene biguanide KW - experimental visceral leishmaniasis KW - drug-delivery systems KW - therapy KW - paromomycin Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148162 VL - 9 IS - 10 ER - TY - JOUR A1 - Neumann, Yvonne A1 - Ohlsen, Knut A1 - Donat, Stefanie A1 - Engelmann, Susanne A1 - Kusch, Harald A1 - Albrecht, Dirk A1 - Cartron, Michael A1 - Hurd, Alexander A1 - Foster, Simon J. T1 - The effect of skin fatty acids on Staphylococcus aureus JF - Archives of Microbiology N2 - Staphylococcus aureus is a commensal of the human nose and skin. Human skin fatty acids, in particular cis-6-hexadecenoic acid (C-6-H), have high antistaphylococcal activity and can inhibit virulence determinant production. Here, we show that sub-MIC levels of C-6-H result in induction of increased resistance. The mechanism(s) of C-6-H activity was investigated by combined transcriptome and proteome analyses. Proteome analysis demonstrated a pleiotropic effect of C-6-H on virulence determinant production. In response to C-6-H, transcriptomics revealed altered expression of over 500 genes, involved in many aspects of virulence and cellular physiology. The expression of toxins (hla, hlb, hlgBC) was reduced, whereas that of host defence evasion components (cap, sspAB, katA) was increased. In particular, members of the SaeRS regulon had highly reduced expression, and the use of specific mutants revealed that the effect on toxin production is likely mediated via SaeRS KW - S. aureus KW - skin fatty acid KW - C-6-H KW - resistance Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121657 VL - 197 ER - TY - JOUR A1 - Sass, Andrea M. A1 - Van Acker, Heleen A1 - Förstner, Konrad U. A1 - Van Nieuwerburgh, Filip A1 - Deforce, Dieter A1 - Vogel, Jörg A1 - Coenye, Tom T1 - Genome-wide transcription start site profiling in biofilm-grown Burkholderia cenocepacia J2315 JF - BMC Genomics N2 - Background: Burkholderia cenocepacia is a soil-dwelling Gram-negative Betaproteobacterium with an important role as opportunistic pathogen in humans. Infections with B. cenocepacia are very difficult to treat due to their high intrinsic resistance to most antibiotics. Biofilm formation further adds to their antibiotic resistance. B. cenocepacia harbours a large, multi-replicon genome with a high GC-content, the reference genome of strain J2315 includes 7374 annotated genes. This study aims to annotate transcription start sites and identify novel transcripts on a whole genome scale. Methods: RNA extracted from B. cenocepacia J2315 biofilms was analysed by differential RNA-sequencing and the resulting dataset compared to data derived from conventional, global RNA-sequencing. Transcription start sites were annotated and further analysed according to their position relative to annotated genes. Results: Four thousand ten transcription start sites were mapped over the whole B. cenocepacia genome and the primary transcription start site of 2089 genes expressed in B. cenocepacia biofilms were defined. For 64 genes a start codon alternative to the annotated one was proposed. Substantial antisense transcription for 105 genes and two novel protein coding sequences were identified. The distribution of internal transcription start sites can be used to identify genomic islands in B. cenocepacia. A potassium pump strongly induced only under biofilm conditions was found and 15 non-coding small RNAs highly expressed in biofilms were discovered. Conclusions: Mapping transcription start sites across the B. cenocepacia genome added relevant information to the J2315 annotation. Genes and novel regulatory RNAs putatively involved in B. cenocepacia biofilm formation were identified. These findings will help in understanding regulation of B. cenocepacia biofilm formation. KW - persistence KW - genomic islands KW - pathogen KW - identification KW - bacteria KW - small RNAs KW - translation initiation KW - cepedia complex KW - global gene expression KW - SEQ KW - resistance KW - burkholderia cenocepacia KW - biofilms KW - dRNA-Seq KW - transcription start site KW - antisense RNA Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139748 VL - 16 IS - 775 ER - TY - JOUR A1 - Singh, Amit K. A1 - Kingston, Joseph J. A1 - Gupta, Shishir K. A1 - Batra, Harsh V. T1 - Recombinant Bivalent Fusion Protein rVE Induces CD4+ and CD8+ T-Cell Mediated Memory Immune Response for Protection Against Yersinia enterocolitica Infection JF - Frontiers in Microbiology N2 - Studies investigating the correlates of immune protection against Yersinia infection have established that both humoral and cell mediated immune responses are required for the comprehensive protection. In our previous study, we established that the bivalent fusion protein (rVE) comprising immunologically active regions of Y pestis LcrV (100-270 aa) and YopE (50-213 aa) proteins conferred complete passive and active protection against lethal Y enterocolitica 8081 challenge. In the present study, cohort of BALB/c mice immunized with rVE or its component proteins rV, rE were assessed for cell mediated immune responses and memory immune protection against Y enterocolitica 8081 rVE immunization resulted in extensive proliferation of both CD4 and CD8 T cell subsets; significantly high antibody titer with balanced IgG1: IgG2a/IgG2b isotypes (1:1 ratio) and up regulation of both Th1 (INF-\(\alpha\), IFN-\(\gamma\), IL 2, and IL 12) and Th2 (IL 4) cytokines. On the other hand, rV immunization resulted in Th2 biased IgG response (11:1 ratio) and proliferation of CD4+ T-cell; rE group of mice exhibited considerably lower serum antibody titer with predominant Th1 response (1:3 ratio) and CD8+ T-cell proliferation. Comprehensive protection with superior survival (100%) was observed among rVE immunized mice when compared to the significantly lower survival rates among rE (37.5%) and rV (25%) groups when IP challenged with Y enterocolitica 8081 after 120 days of immunization. Findings in this and our earlier studies define the bivalent fusion protein rVE as a potent candidate vaccine molecule with the capability to concurrently stimulate humoral and cell mediated immune responses and a proof of concept for developing efficient subunit vaccines against Gram negative facultative intracellular bacterial pathogens. KW - I-tasser KW - Yersinia enterocolitica KW - memory immune responses KW - cytokine profiling KW - CD8+T cells KW - CD4+T cells KW - recombinant protein rVE KW - resistance KW - pneumonic plague KW - pestis infection KW - nonhuman-primates KW - III secretion KW - V-antigen KW - mice KW - vaccine Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136114 VL - 6 IS - 1407 ER - TY - JOUR A1 - Kaiser, Bettina A1 - Vogg, Gerd A1 - Fürst, Ursula B. A1 - Albert, Markus T1 - Parasitic plants of the genus Cuscuta and their interaction with susceptible and resistant host plants JF - Frontiers in Plant Science N2 - By comparison with plant microbe interaction, little is known about the interaction of parasitic plants with their hosts. Plants of the genus Cuscuta belong to the family of Cuscutaceae and comprise about 200 species, all of which live as stem holoparasites on other plants. Cuscuta spp. possess no roots nor fully expanded leaves and the vegetative portion appears to be a stem only. The parasite winds around plants and penetrates the host stems via haustoria, forming direct connections to the vascular bundles of their hosts to withdraw water, carbohydrates, and other solutes. Besides susceptible hosts, a few plants exist that exhibit an active resistance against infestation by Cuscuta spp. For example, cultivated tomato (Solanum lycopersicum) fends off Cuscuta reflexa by means of a hypersensitive-type response occurring in the early penetration phase. This report on the plant plant dialog between Cuscuta spp. and its host plants focuses on the incompatible interaction of C. reflexa with tomato. KW - incompatible interaction KW - messenger-RNA KW - Reflexa Roxb KW - localization KW - symbiosis KW - parasitic plants KW - plant-plant interaction KW - Cuscuta KW - dodder KW - plant immunity KW - resistance KW - Lycopersicon esculentum KW - phenolic constituents KW - Orobanche crenata KW - weed dodder KW - tomato KW - striga Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144091 VL - 6 IS - 45 ER - TY - JOUR A1 - Dühring, Sybille A1 - Germerodt, Sebastian A1 - Skerka, Christine A1 - Zipfel, Peter F. A1 - Dandekar, Thomas A1 - Schuster, Stefan T1 - Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies JF - Frontiers in Microbiology N2 - The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given. KW - agent-based model KW - antimicrobial peptides KW - fungal pathogens KW - Candida albicans KW - immunological cross-talk KW - beta-lactamase inhibition KW - in vitro KW - biomaterial surfaces KW - biofilm formation KW - dendritic cells KW - infection KW - resistance KW - human immune system KW - host-pathogen interaction KW - computational systems biology KW - defense and evasion strategies Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151621 VL - 6 IS - 625 ER -