@article{MoremiClausMshana2016, author = {Moremi, Nyambura and Claus, Heike and Mshana, Stephen E.}, title = {Antimicrobial resistance pattern: a report of microbiological cultures at a tertiary hospital in Tanzania}, series = {BMC Infectious Diseases}, volume = {16}, journal = {BMC Infectious Diseases}, number = {756}, doi = {10.1186/s12879-016-2082-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161185}, year = {2016}, abstract = {Background Antimicrobial resistance has been declared by the World Health Organization as a threat to the public health. The aim of this study was to analyze antimicrobial resistance patterns of the common pathogens occurring at the Bugando Medical Centre (BMC), Mwanza, Tanzania to provide data for antimicrobial stewardship programmes. Methods A total of 3330 microbiological culture results scripts representing non-repetitive specimens reported between June 2013 and May 2015 were retrieved and analyzed for pathogens and their susceptibility patterns using STATA-11 software. Results Out of 3330 specimens, 439 (13.2\%) had positive culture. Staphylococcus aureus (n = 100; 22.8\%), Klebsiella pneumoniae (n = 65; 14.8\%) and Escherichia coli (n = 41; 9.3\%) were the most frequently isolated bacteria. Of 78 Staphylococcus aureus tested, 27 (34.6\%) were found to be methicillin resistant Staphylococcus aureus (MRSA). Rates of resistance of Klebsiella pneumoniae and Escherichia coli isolates to third generation cephalosporins were 38.5\% (25/65) and 29.3\% (12/41) respectively. Staphylococcus aureus and Klesbiella pneumoniae were commonly isolated from bloodstream infections while Escherichia coli and Pseudomonas aeruginosa were the predominant isolates from urinary tract and wounds infections respectively. Of 23 Salmonella species isolated, 22 (95\%) were recovered from the blood. Nine of the 23 Salmonella species isolates (39\%) were found to be resistant to third generation cephalosporins. The resistance rate of gram-negative bacteria to third generation cephalosporins increased from 26.5\% in 2014 to 57.9\% in 2015 (p = 0.004) while the rate of MRSA decreased from 41.2\% in 2013 to 9.5\% in 2015 (p = 0.016). Multidrug-resistant gram-negative isolates were commonly isolated from Intensive Care Units and it was noted that, the majority of invasive infections were due to gram-negative bacteria. Conclusion There is an increase in proportion of gram-negative isolates resistant to third generation cephalosporins. The diversity of potential pathogens resistant to commonly prescribed antibiotics underscores the importance of sustained and standardized antimicrobial resistance surveillance and antibiotic stewardship programmes in developing countries.}, language = {en} } @article{MarincolaLiongSchoenetal.2021, author = {Marincola, Gabriella and Liong, Olivia and Schoen, Christoph and Abouelfetouh, Alaa and Hamdy, Aisha and Wencker, Freya D. R. and Marciniak, Tessa and Becker, Karsten and K{\"o}ck, Robin and Ziebuhr, Wilma}, title = {Antimicrobial Resistance Profiles of Coagulase-Negative Staphylococci in Community-Based Healthy Individuals in Germany}, series = {Frontiers in Public Health}, volume = {9}, journal = {Frontiers in Public Health}, issn = {2296-2565}, doi = {10.3389/fpubh.2021.684456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240881}, year = {2021}, abstract = {Coagulase-negative staphylococci (CoNS) are common opportunistic pathogens, but also ubiquitous human and animal commensals. Infection-associated CoNS from healthcare environments are typically characterized by pronounced antimicrobial resistance (AMR) including both methicillin- and multidrug-resistant isolates. Less is known about AMR patterns of CoNS colonizing the general population. Here we report on AMR in commensal CoNS recovered from 117 non-hospitalized volunteers in a region of Germany with a high livestock density. Among the 69 individuals colonized with CoNS, 29 had reported contacts to either companion or farm animals. CoNS were selectively cultivated from nasal swabs, followed by species definition by 16S rDNA sequencing and routine antibiotic susceptibility testing. Isolates displaying phenotypic AMR were further tested by PCR for presence of selected AMR genes. A total of 127 CoNS were isolated and Staphylococcus epidermidis (75\%) was the most common CoNS species identified. Nine isolates (7\%) were methicillin-resistant (MR) and carried the mecA gene, with seven individuals (10\%) being colonized with at least one MR-CoNS isolate. While resistance against gentamicin, phenicols and spectinomycin was rare, high resistance rates were found against tetracycline (39\%), erythromycin (33\%) and fusidic acid (24\%). In the majority of isolates, phenotypic resistance could be associated with corresponding AMR gene detection. Multidrug-resistance (MDR) was observed in 23\% (29/127) of the isolates, with 33\% (23/69) of the individuals being colonized with MDR-CoNS. The combined data suggest that MR- and MDR-CoNS are present in the community, with previous animal contact not significantly influencing the risk of becoming colonized with such isolates.}, language = {en} } @article{TappeHaeuplerSchaeferetal.2013, author = {Tappe, Dennis and Haeupler, Alexandra and Sch{\"a}fer, Hansj{\"o}rg and Racz, Paul and Cramer, Jakob P. and Poppert, Sven}, title = {Armillifer armillatus Pentastomiasis in African Immigrant, Germany}, series = {Emerging Infectious Diseases}, volume = {19}, journal = {Emerging Infectious Diseases}, number = {3}, doi = {10.3201/eid1903.121508}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129054}, pages = {507-508}, year = {2013}, abstract = {No abstract available.}, language = {en} } @article{DrayssClausHubertetal.2019, author = {Drayß, Maria and Claus, Heike and Hubert, Kerstin and Thiel, Katrin and Berger, Anja and Sing, Andreas and van der Linden, Mark and Vogel, Ulrich and L{\^a}m, Thi{\^e}n-Tr{\´i}}, title = {Asymptomatic carriage of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Group A Streptococcus and Staphylococcus aureus among adults aged 65 years and older}, series = {PLoS ONE}, volume = {14}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0212052}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201042}, pages = {e0212052}, year = {2019}, abstract = {Objective The aim of this study was to determine the prevalence of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, group A Streptococcus (GAS), and Staphylococcus aureus in asymptomatic elderly people and to unravel risk factors leading to colonization. Methods A multi-centre cross-sectional study was conducted including 677 asymptomatic adults aged 65 years or more, living at home or in nursing homes. Study areas were Greater Aachen (North-Rhine-Westphalia) and Wuerzburg (Bavaria), both regions with medium to high population density. Nasal and oropharyngeal swabs as well as questionnaires were collected from October 2012 to May 2013. Statistical analysis included multiple logistic regression models. Results The carriage rate was 1.9\% ([95\%CI: 1.0-3.3\%]; 13/677) for H. influenzae, 0.3\% ([95\%CI: 0-1.1\%]; 2/677) for N. meningitidis and 0\% ([95\% CI: 0-0.5\%]; 0/677) for S. pneumoniae and GAS. Staphylococcus aureus was harboured by 28.5\% of the individuals ([95\% CI: 25.1-32.1\%]; 193/677) and 0.7\% ([95\% CI: 0.2-1.7\%]; 5/677) were positive for methicillin-resistant S. aureus. Among elderly community-dwellers colonization with S. aureus was significantly associated with higher educational level (adjusted OR: 1.905 [95\% CI: 1.248-2.908]; p = 0.003). Among nursing home residents colonization was associated with being married (adjusted OR: 3.367 [1.502-7.546]; p = 0.003). Conclusion The prevalence of N. meningitidis, H. influenzae, S. pneumoniae and GAS was low among older people in Germany. The S. aureus rate was expectedly high, while MRSA was found in less than 1\% of the individuals.}, language = {en} } @article{AlZabenMedyukhinaDietrichetal.2019, author = {Al-Zaben, Naim and Medyukhina, Anna and Dietrich, Stefanie and Marolda, Alessandra and H{\"u}nniger, Kerstin and Kurzai, Oliver and Figge, Marc Thilo}, title = {Automated tracking of label-free cells with enhanced recognition of whole tracks}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-39725-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221093}, year = {2019}, abstract = {Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.}, language = {en} } @article{SchlesingerWeissbrichWedekinketal.2020, author = {Schlesinger, Tobias and Weißbrich, Benedikt and Wedekink, Florian and Notz, Quirin and Herrmann, Johannes and Krone, Manuel and Sitter, Magdalena and Schmid, Benedikt and Kredel, Markus and Stumpner, Jan and D{\"o}lken, Lars and Wischhusen, J{\"o}rg and Kranke, Peter and Meybohm, Patrick and Lotz, Christpher}, title = {Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study}, series = {PLoS One}, volume = {15, 2020}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0242917}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231348}, year = {2020}, abstract = {Background The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). Methods This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. Results Most patients (91\%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30\%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100\% of the cases, oropharyngeal swabs only in 77\%. Blood samples were positive in 26\% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). Conclusions COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.}, language = {en} } @article{StraubStapfFischeretal.2022, author = {Straub, Anton and Stapf, Maximilian and Fischer, Markus and Vollmer, Andreas and Linz, Christian and L{\^a}m, Thi{\^e}n-Tr{\´i} and K{\"u}bler, Alexander and Brands, Roman C. and Scherf-Clavel, Oliver and Hartmann, Stefan}, title = {Bone concentration of ampicillin/sulbactam: a pilot study in patients with osteonecrosis of the jaw}, series = {International Journal of Environmental Research and Public Health}, volume = {19}, journal = {International Journal of Environmental Research and Public Health}, number = {22}, issn = {1660-4601}, doi = {10.3390/ijerph192214917}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297413}, year = {2022}, abstract = {Osteonecrosis of the jaw (ONJ) occurs typically after irradiation of the head and neck area or after the intake of antiresorptive agents. Both interventions can lead to compromised bone perfusion and can ultimately result in infection and necrosis. Treatment usually consists of surgical necrosectomy and prolonged antibiotic therapy, usually through beta-lactams such as ampicillin/sulbactam. The poor blood supply in particular raises the question as to whether this form of antibiosis can achieve sufficient concentrations in the bone. Therefore, we investigated the antibiotic concentration in plasma and bone samples in a prospective study. Bone samples were collected from the necrosis core and in the vital surrounding bone. The measured concentrations in plasma for ampicillin and sulbactam were 126.3 ± 77.6 and 60.2 ± 35.0 µg/mL, respectively. In vital bone and necrotic bone samples, the ampicillin/sulbactam concentrations were 6.3 ± 7.8/1.8 ± 2.0 µg/g and 4.9 ± 7.0/1.7 ± 1.7 µg/g, respectively. These concentrations are substantially lower than described in the literature. However, the concentration seems sufficient to kill most bacteria, such as Streptococci and Staphylococci, which are mostly present in the biofilm of ONJ. We, therefore, conclude that intravenous administration of ampicillin/sulbactam remains a valuable treatment in the therapy of ONJ. Nevertheless, increasing resistance of Escherichia coli towards beta-lactam antibiotics have been reported and should be considered.}, language = {en} } @article{MaidenFrosch2012, author = {Maiden, Martin C. J. and Frosch, Matthias}, title = {Can we, should we, eradicate the meningococcus?}, series = {Vaccine}, volume = {30}, journal = {Vaccine}, number = {Suppl. 2}, doi = {10.1016/j.vaccine.2011.12.068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125646}, pages = {B52-B56}, year = {2012}, abstract = {The eradication of infectious agents is an attractive means of disease control that, to date, has been achieved for only one human pathogen, the smallpox virus. The introduction of vaccines against Neisseria meningitidis into immunisation schedules, and particularly the conjugate polysaccharide vaccines which can interrupt transmission, raises the question of whether disease caused by this obligate human bacterium can be controlled, eliminated, or even eradicated. The limited number of meningococcal serogroups, lack of an animal reservoir, and importance of meningococcal disease are considerations in favour of eradication; however, the commensal nature of most infections, the high diversity of meningococcal populations, and the lack of comprehensive vaccines are all factors that suggest that this is not feasible. Indeed, any such attempt might be harmful by perturbing the human microbiome and its interaction with the immune system. On balance, the control and possible elimination of disease caused by particular disease-associated meningococcal genotypes is a more achievable and worthwhile goal.}, language = {en} } @article{ApsemidouFuellerIdelevichetal.2020, author = {Apsemidou, Athanasia and F{\"u}ller, Miriam Antonie and Idelevich, Evgeny A. and Kurzai, Oliver and Tragiannidis, Athanasios and Groll, Andreas H.}, title = {Candida lusitaniae breakthrough fungemia in an immuno-compromised adolescent: case report and review of the literature}, series = {Journal of Fungi}, volume = {6}, journal = {Journal of Fungi}, number = {4}, issn = {2309-608X}, doi = {10.3390/jof6040380}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220125}, year = {2020}, abstract = {Candida lusitaniae is a rare cause of candidemia that is known for its unique capability to rapidly acquire resistance to amphotericin B. We report the case of an adolescent with grade IV graft-vs.-host disease after hematopoietic cell transplantation who developed catheter-associated C. lusitaniae candidemia while on therapeutic doses of liposomal amphotericin B. We review the epidemiology of C. lusitaniae bloodstream infections in adult and pediatric patients, the development of resistance, and its role in breakthrough candidemia. Appropriate species identification, in vitro susceptibility testing, and source control are pivotal to optimal management of C. lusitaniae candidemia. Initial antifungal therapy may consist of an echinocandin and be guided by in vitro susceptibility and clinical response.}, language = {en} } @article{PageWallstabeLotheretal.2021, author = {Page, Lukas and Wallstabe, Julia and Lother, Jasmin and Bauser, Maximilian and Kniemeyer, Olaf and Strobel, Lea and Voltersen, Vera and Teutschbein, Janka and Hortschansky, Peter and Morton, Charles Oliver and Brakhage, Axel A. and Topp, Max and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen}, title = {CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus}, series = {Frontiers in Immunology}, volume = {12}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2021.659752}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239493}, year = {2021}, abstract = {Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4\(^+\) and CD8\(^+\) T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.}, language = {en} } @article{SlaninaHeblingHaucketal.2012, author = {Slanina, Heiko and Hebling, Sabrina and Hauck, Christoph R. and Schubert-Unkmeir, Alexandra}, title = {Cell Invasion by Neisseria meningitidis Requires a Functional Interplay between the Focal Adhesion Kinase, Src and Cortactin}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75354}, year = {2012}, abstract = {Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90\%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells.}, subject = {Medizin}, language = {en} } @article{NieuwenhuizenEvans2022, author = {Nieuwenhuizen, Natalie E. and Evans, Joanna C.}, title = {Cellular and molecular mechanisms in mycobacterial infection}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {13}, issn = {1422-0067}, doi = {10.3390/ijms23137205}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284370}, year = {2022}, abstract = {No abstract available}, language = {en} } @article{LichteneggerBinaRoieretal.2014, author = {Lichtenegger, Sabine and Bina, Isabelle and Roier, Sandro and Bauernfeind, Stilla and Keidel, Kristina and Schild, Stefan and Anthony, Mark and Reidl, Joachim}, title = {Characterization of lactate utilization and its implication on the physiology of Haemophilus influenzae}, series = {International Journal of Medical Microbiology}, volume = {304}, journal = {International Journal of Medical Microbiology}, number = {3-4}, doi = {10.1016/j.ijmm.2014.02.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121335}, pages = {490-8}, year = {2014}, abstract = {Haemophilus influenzae is a Gram-negative bacillus and a frequent commensal of the human nasopharynx. Earlier work demonstrated that in H. influenzae type b, l-lactate metabolism is associated with serum resistance and in vivo survival of the organism. To further gain insight into lactate utilization of the non-typeable (NTHi) isolate 2019 and laboratory prototype strain Rd KW20, deletion mutants of the l-lactate dehydrogenase (lctD) and permease (lctP) were generated and characterized. It is shown, that the apparent KM of l-lactate uptake is 20.1μM as determined for strain Rd KW20. Comparison of the COPD isolate NTHi 2019-R with the corresponding lctP knockout strain for survival in human serum revealed no lactate dependent serum resistance. In contrast, we observed a 4-fold attenuation of the mutant strain in a murine model of nasopharyngeal colonization. Characterization of lctP transcriptional control shows that the lactate utilization system in H. influenzae is not an inductor inducible system. Rather negative feedback regulation was observed in the presence of l-lactate and this is dependent on the ArcAB regulatory system. Additionally, for 2019 it was found that lactate may have signaling function leading to increased cell growth in late log phase under conditions where no l-lactate is metabolized. This effect seems to be ArcA independent and was not observed in strain Rd KW20. We conclude that l-lactate is an important carbon-source and may act as host specific signal substrate which fine tunes the globally acting ArcAB regulon and may additionally affect a yet unknown signaling system and thus may contribute to enhanced in vivo survival.}, language = {en} } @phdthesis{Pasquet2014, author = {Pasquet, Vivian}, title = {Characterization of thioredoxin and glutathione reductase activities of Mesocestoides vogae, a flatworm parasite useful as a laboratory model for the screening of drugs.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-106759}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {Flatworm parasites (platyhelminths) cause serious infection diseases in humans, such as schistosomiasis and hydatid disease, mainly prevalent in developing countries. However, the current repertoire of drug armamentarium used to combat flatworm infections is limited. For instance, praziquantel is the only drug available for mass treatment of Schistosoma infections. In contrast to their hosts, flatworm parasites possess a distinct redox arrangement of redox pathways in which the selenoenzyme thioredoxin glutathione reductase (TGR) controls the overall redox homeostasis. Interference with this enzyme leads to parasite death. Hence, this key redox enzyme seems to be a new promising drug target against flatworm infections. Because most flatworms are difficult to cultivate in the laboratory (e.g. Echinococcus granulosus experimental infection in mice takes about 10 month to develop into cysts), this work was focused on Mesocestoides vogae (syn. corti), a non-human flatworm parasite which is an interesting laboratory model to study other flatworm infections: it is very rare in humans, can be easily manipulated both in vivo and in vitro and grows extremely fast in mice. With the aim to assess TGR inhibitors as possible drugs to treat flatworm infections, the thioredoxin and glutathione pathways of M.vogae were studied. Here, the objectives were to study whether the biochemical pathways that maintain the redox homeostasis in M. vogae conform to the general biochemical scenario proposed for other platyhelminth parasites. Here, it was proven that M. vogae extracts possess both thioredoxin and glutathione reductase activities. The thioredoxin and glutathione reductase activities were partially purified from total extracts by a combination of ammonium sulfate precipitation, anion exchange and hydroxyapatite chromatography. Both activities co-purified in all steps which strongly indicates the existence of TGR rather than a single TR and GR. Furthermore partially purified activities could be inhibited by the organogold compound auranofin, a known TGR inhibitor. Moreover, the glutathione reductase activity displays hysteresis (a peculiar kinetic behavior) at high concentrations of oxidised glutathione, a feature typical of flatworm TGRs, but not of conventional GR. Although M. vogae activities could not be purified to homogeneity, the overall results strongly indicate that this flatworm possesses TGR and lacks conventional GR and TR. Furthermore the thiadiazole WPQ75 and the N-oxide VL16E (a furoxan derivate) were identified as inhibitors of TGR activity of M.vogae at a 10 µM concentration. These inhibitors were able to kill M.vogae larval worms in vitro as well as in experimental infection in mice. Due to the existence of TGR activity in M.vogae, the possibility to inhibit this activity with recently discovered inhibitors of flatworm TGR and the successes achieved by testing these inhibitors both in vitro and in vivo, it is strongly evident that M. vogae would be an excellent model to assess TGR inhibitors in flatworm infections.}, subject = {Thioredoxin}, language = {en} } @article{BeckMorbachBeeretal.2010, author = {Beck, Christine and Morbach, Henner and Beer, Meinrad and Stenzel, Martin and Tappe, Dennis and Gattenl{\"o}hner, Stefan and Hofmann, Ulrich and Raab, Peter and Girschick, Hermann J.}, title = {Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67792}, year = {2010}, abstract = {Introduction: Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported. Methods: Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome. Results: Naproxen treatment was highly effective in general, inducing a symptom-free status in 43\% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67\% of them were clinically silent. Conclusions: Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.}, subject = {Mikrobiologie}, language = {en} } @article{CucherMaricontiManciullietal.2023, author = {Cucher, Marcela A. and Mariconti, Mara and Manciulli, Tommaso and Vola, Ambra and Rosenzvit, Mara C. and Brehm, Klaus and Kamenetzky, Laura and Brunetti, Enrico}, title = {Circulating small RNA profiling of patients with alveolar and cystic echinococcosis}, series = {Biology}, volume = {12}, journal = {Biology}, number = {5}, issn = {2079-7737}, doi = {10.3390/biology12050715}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319270}, year = {2023}, abstract = {Alveolar (AE) and cystic (CE) echinococcosis are two parasitic diseases caused by the tapeworms Echinococcus multilocularis and E. granulosus sensu lato (s. l.), respectively. Currently, AE and CE are mainly diagnosed by means of imaging techniques, serology, and clinical and epidemiological data. However, no viability markers that indicate parasite state during infection are available. Extracellular small RNAs (sRNAs) are short non-coding RNAs that can be secreted by cells through association with extracellular vesicles, proteins, or lipoproteins. Circulating sRNAs can show altered expression in pathological states; hence, they are intensively studied as biomarkers for several diseases. Here, we profiled the sRNA transcriptomes of AE and CE patients to identify novel biomarkers to aid in medical decisions when current diagnostic procedures are inconclusive. For this, endogenous and parasitic sRNAs were analyzed by sRNA sequencing in serum from disease negative, positive, and treated patients and patients harboring a non-parasitic lesion. Consequently, 20 differentially expressed sRNAs associated with AE, CE, and/or non-parasitic lesion were identified. Our results represent an in-depth characterization of the effect E. multilocularis and E. granulosus s. l. exert on the extracellular sRNA landscape in human infections and provide a set of novel candidate biomarkers for both AE and CE detection.}, language = {en} } @article{PetersKaiserFinketal.2021, author = {Peters, Simon and Kaiser, Lena and Fink, Julian and Schumacher, Fabian and Perschin, Veronika and Schlegel, Jan and Sauer, Markus and Stigloher, Christian and Kleuser, Burkhard and Seibel, Juergen and Schubert-Unkmeir, Alexandra}, title = {Click-correlative light and electron microscopy (click-AT-CLEM) for imaging and tracking azido-functionalized sphingolipids in bacteria}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-83813-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259147}, pages = {4300}, year = {2021}, abstract = {Sphingolipids, including ceramides, are a diverse group of structurally related lipids composed of a sphingoid base backbone coupled to a fatty acid side chain and modified terminal hydroxyl group. Recently, it has been shown that sphingolipids show antimicrobial activity against a broad range of pathogenic microorganisms. The antimicrobial mechanism, however, remains so far elusive. Here, we introduce 'click-AT-CLEM', a labeling technique for correlated light and electron microscopy (CLEM) based on the super-resolution array tomography (srAT) approach and bio-orthogonal click chemistry for imaging of azido-tagged sphingolipids to directly visualize their interaction with the model Gram-negative bacterium Neisseria meningitidis at subcellular level. We observed ultrastructural damage of bacteria and disruption of the bacterial outer membrane induced by two azido-modified sphingolipids by scanning electron microscopy and transmission electron microscopy. Click-AT-CLEM imaging and mass spectrometry clearly revealed efficient incorporation of azido-tagged sphingolipids into the outer membrane of Gram-negative bacteria as underlying cause of their antimicrobial activity.}, language = {en} } @article{AbimannanSumathiKrishnarajasekharetal.2019, author = {Abimannan, Nagarajan and Sumathi, G. and Krishnarajasekhar, O. R. and Sinha, Bhanu and Krishnan, Padma}, title = {Clonal Clusters and Virulence Factors of Methicillin-Resistant \(Staphylococcus\) \(Aureus\): Evidence for Community-Acquired Methicillin-Resistant \(Staphylococcus\) \(Aureus\) Infiltration into Hospital Settings in Chennai, South India}, series = {Indian Journal of Medical Microbiology}, volume = {37}, journal = {Indian Journal of Medical Microbiology}, number = {3}, doi = {10.4103/ijmm.IJMM_18_271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226963}, pages = {326-336}, year = {2019}, abstract = {Background and Objective: Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. Methods: S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance. Results and Conclusion: A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17\%, 81.67\%, 58.33\% and 22.85\% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings.}, language = {en} } @article{KoziolJareroOlsonetal.2016, author = {Koziol, Uriel and Jarero, Francesca and Olson, Peter D. and Brehm, Klaus}, title = {Comparative analysis of Wnt expression identifies a highly conserved developmental transition in flatworms}, series = {BMC Biology}, volume = {14}, journal = {BMC Biology}, number = {10}, doi = {10.1186/s12915-016-0233-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146566}, year = {2016}, abstract = {Background Early developmental patterns of flatworms are extremely diverse and difficult to compare between distant groups. In parasitic flatworms, such as tapeworms, this is confounded by highly derived life cycles involving indirect development, and even the true orientation of the tapeworm antero-posterior (AP) axis has been a matter of controversy. In planarians, and metazoans generally, the AP axis is specified by the canonical Wnt pathway, and we hypothesized that it could also underpin axial formation during larval metamorphosis in tapeworms. Results By comparative gene expression analysis of Wnt components and conserved AP markers in the tapeworms Echinococcus multilocularis and Hymenolepis microstoma, we found remarkable similarities between the early stages of larval metamorphosis in tapeworms and late embryonic and adult development in planarians. We demonstrate posterior expression of specific Wnt factors during larval metamorphosis and show that scolex formation is preceded by localized expression of Wnt inhibitors. In the highly derived larval form of E. multilocularis, which proliferates asexually within the mammalian host, we found ubiquitous expression of posterior Wnt factors combined with localized expression of Wnt inhibitors that correlates with the asexual budding of scoleces. As in planarians, muscle cells are shown to be a source of secreted Wnt ligands, providing an explanation for the retention of a muscle layer in the immotile E. multilocularis larva. Conclusions The strong conservation of gene expression between larval metamorphosis in tapeworms and late embryonic development in planarians suggests, for the first time, a homologous developmental period across this diverse phylum. We postulate these to represent the phylotypic stages of these flatworm groups. Our results support the classical notion that the scolex is the true anterior end of tapeworms. Furthermore, the up-regulation of Wnt inhibitors during the specification of multiple anterior poles suggests a mechanism for the unique asexual reproduction of E. multilocularis larvae.}, language = {en} } @article{KlughammerDittrichBlometal.2017, author = {Klughammer, Johanna and Dittrich, Marcus and Blom, Jochen and Mitesser, Vera and Vogel, Ulrich and Frosch, Matthias and Goesmann, Alexander and M{\"u}ller, Tobias and Schoen, Christoph}, title = {Comparative genome sequencing reveals within-host genetic changes in Neisseria meningitidis during invasive disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0169892}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159547}, pages = {e0169892}, year = {2017}, abstract = {Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.}, language = {en} }