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      1. Author :
        Xiong, Y. Q.; Willard, J.; Kadurugamuwa, J. L.; Yu, J.; Francis, K. P.; Bayer, A. S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Antimicrobial Agents and Chemotherapy
      6. Products :
      7. Volume :
        49
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen; Bioware; Xen29
      12. Abstract :
        Therapeutic options for invasive Staphylococcus aureus infections have become limited due to rising antimicrobial resistance, making relevant animal model testing of new candidate agents more crucial than ever. In the present studies, a rat model of aortic infective endocarditis (IE) caused by a bioluminescently engineered, biofilm-positive S. aureus strain was used to evaluate real-time antibiotic efficacy directly. This strain was vancomycin and cefazolin susceptible but gentamicin resistant. Bioluminescence was detected and quantified daily in antibiotic-treated and control animals with IE, using a highly sensitive in vivo imaging system (IVIS). Persistent and increasing cardiac bioluminescent signals (BLS) were observed in untreated animals. Three days of vancomycin therapy caused significant reductions in both cardiac BLS (>10-fold versus control) and S. aureus densities in cardiac vegetations (P < 0.005 versus control). However, 3 days after discontinuation of vancomycin therapy, a greater than threefold increase in cardiac BLS was observed, indicating relapsing IE (which was confirmed by quantitative culture). Cefazolin resulted in modest decreases in cardiac BLS and bacterial densities. These microbiologic and cardiac BLS differences during therapy correlated with a longer time-above-MIC for vancomycin (>12 h) than for cefazolin (?4 h). Gentamicin caused neither a reduction in cardiac S. aureus densities nor a reduction in BLS. There were significant correlations between cardiac BLS and S. aureus densities in vegetations in all treatment groups. These data suggest that bioluminescent imaging provides a substantial advance in the real-time monitoring of the efficacy of therapy of invasive S. aureus infections in live animals.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15743898
      14. Call Number :
        144577
      15. Serial :
        7474
      1. Author :
        Yu, Jun; Wu, Jenny; Francis, Kevin P; Purchio, Tony F; Kadurugamuwa, Jagath L
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        The Journal of antimicrobial chemotherapy
      6. Products :
      7. Volume :
        55
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Biofilms; Bioware; Drug Resistance, Bacterial; Mice; Mutation; Rifampin; Staphylococcus aureus; Xen29
      12. Abstract :
        OBJECTIVES To investigate in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm model using bioluminescence imaging. MATERIALS AND METHODS S. aureus was engineered with a luciferase operon to emit bioluminescence that can be detected in vivo using an IVIS imaging system. Two rifampicin-resistant strains of S. aureus that were previously isolated from animals undergoing rifampicin treatment, S464P (resistant to low concentrations of rifampicin) and H481Y (resistant to high concentrations of rifampicin), were characterized and then compared with their parental strain for in vivo fitness to form biofilm infections in the absence of rifampicin. RESULTS The mutant S464P showed better adaptation to in vivo growth than either the parental strain or H481Y without selective pressure. Six days after implanting pre-colonized catheters, bioluminescent signals were seen from 100% of the catheters coated by the mutant S464P. In comparison, only 83% and 61% of the catheters coated by the parental strain and H481Y, respectively, maintained a signal in vivo. Rifampicin treatment of S464P biofilms in vivo resulted in a slight decline, but earlier rebound in bioluminescence from these catheters compared with the parental signal, whereas rifampicin had no affect on bioluminescence in mice infected with mutant H481Y. CONCLUSIONS The mutant with low-level rifampicin resistance appears to be better adapted to in vivo growth than the mutant that has high-level rifampicin resistance. Moreover, the former mutant may actually have a slight competitive advantage over the rifampicin-susceptible strain (parental), raising awareness for the occurrence of such strains in clinical environments.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15743898
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9055
      1. Author :
        Georgel, Philippe; Crozat, Karine; Lauth, Xavier; Makrantonaki, Evgenia; Seltmann, Holger; Sovath, Sosathya; Hoebe, Kasper; Du, Xin; Rutschmann, Sophie; Jiang, Zhengfan; Bigby, Timothy; Nizet, Victor; Zouboulis, Christos C; Beutler, Bruce
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Chromosome Mapping; Eye Diseases; Fatty Acids, Monounsaturated; Likelihood Functions; Lod Score; Mice; Mice, Inbred C57BL; Oleic Acid; Receptors, Immunologic; Sequence Analysis, DNA; Skin; Staphylococcal Skin Infections; Stearoyl-CoA Desaturase; Streptococcus pyogenes; Time Factors; Toll-Like Receptor 2; Xen8.1, Xen20, Xen14
      12. Abstract :
        flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C(16:1)) and oleate (C(18:1)), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1-a gene with numerous NF-kappaB elements in its promoter--is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16040962
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9990
      1. Author :
        N/A
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Nature
      6. Products :
      7. Volume :
        433
      8. Issue :
        7025
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Aging; Animals; Antigens, CD36; Cell Line; Dimerization; Ethylnitrosourea; Gene Deletion; Glycerides; Homozygote; Humans; Immunologic Deficiency Syndromes; Lipopeptides; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutagenesis; Mutation; Oligopeptides; Peptidoglycan; Phenotype; Receptors, Cell Surface; Signal Transduction; Staphylococcal Infections; Staphylococcus aureus; Toll-Like Receptor 2; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Zymosan
      12. Abstract :
        Toll-like receptor 2 (TLR2) is required for the recognition of numerous molecular components of bacteria, fungi and protozoa. The breadth of the ligand repertoire seems unusual, even if one considers that TLR2 may form heteromers with TLRs 1 and 6 (ref. 12), and it is likely that additional proteins serve as adapters for TLR2 activation. Here we show that an N-ethyl-N-nitrosourea-induced nonsense mutation of Cd36 (oblivious) causes a recessive immunodeficiency phenotype in which macrophages are insensitive to the R-enantiomer of MALP-2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36(obl) macrophages readily detect S-MALP-2, PAM(2)CSK(4), PAM(3)CSK(4) and zymosan, revealing that some--but not all--TLR2 ligands are dependent on CD36. Already known as a receptor for endogenous molecules, CD36 is also a selective and nonredundant sensor of microbial diacylglycerides that signal via the TLR2/6 heterodimer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15690042
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9991
      1. Author :
        Lambrechts, Saskia A G; Demidova, Tatiana N; Aalders, Maurice C G; Hasan, Tayyaba; Hamblin, Michael R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Photochemical & photobiological sciences: Official journal of the European Photochemistry Association and the European Society for Photobiology
      6. Products :
      7. Volume :
        4
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Burns; Mice; Photochemotherapy; Staphylococcal Infections; Staphylococcus aureus; Xen8.1
      12. Abstract :
        The rise of multiply antibiotic resistant bacteria has led to searches for novel antimicrobial therapies to treat infections. Photodynamic therapy (PDT) is a potential candidate; it uses the combination of a photosensitizer with visible light to produce reactive oxygen species that lead to cell death. We used PDT mediated by meso-mono-phenyl-tri(N-methyl-4-pyridyl)-porphyrin (PTMPP) to treat burn wounds in mice with established Staphylococcus aureus infections The third degree burn wounds were infected with bioluminescent S. aureus. PDT was applied after one day of bacterial growth by adding a 25% DMSO/500 microM PTMPP solution to the wound followed by illumination with red light and periodic imaging of the mice using a sensitive camera to detect the bioluminescence. More than 98% of the bacteria were eradicated after a light dose of 210 J cm(-2) in the presence of PTMPP. However, bacterial re-growth was observed. Light alone or PDT both delayed the wound healing. These data suggest that PDT has the potential to rapidly reduce the bacterial load in infected burns. The treatment needs to be optimized to reduce wound damage and prevent recurrence.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15986057
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9993
      1. Author :
        Kadurugamuwa, J. L.; Modi, K.; Yu, J.; Francis, K. P.; Purchio, T.; Contag, P. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Diagnostic Imaging/ methods, Female, Mice, Microscopy, Electron, Scanning, Photons, Proteus Infections/ diagnosis, Proteus mirabilis/drug effects/isolation & purification, Pseudomonas Infections/ diagnosis, Pseudomonas aeruginosa/drug effects/isolation & purification, Urinary Catheterization/ adverse effects, Urinary Tract Infections/ diagnosis IVIS, Xenogen, Xen5, Xen44
      12. Abstract :
        Urinary tract infections (UTIs) are among the most common bacterial infections acquired by humans, particularly in catheterized patients. A major problem with catheterization is the formation of bacterial biofilms on catheter material and the risk of developing persistent UTIs that are difficult to monitor and eradicate. To better understand the course of UTIs and allow more accurate studies of in vivo antibiotic efficacy, we developed a catheter-based biofilm infection model with mice, using bioluminescently engineered bacteria. Two important urinary tract pathogens, Pseudomonas aeruginosa and Proteus mirabilis, were made bioluminescent by stable insertion of a complete lux operon. Segments of catheter material (precolonized or postimplant infected) with either pathogen were placed transurethrally in the lumen of the bladder by using a metal stylet without surgical manipulation. The bioluminescent strains were sufficiently bright to be readily monitored from the outside of infected animals, using a low-light optical imaging system, including the ability to trace the ascending pattern of light-emitting bacteria through ureters to the kidneys. Placement of the catheter in the bladder not only resulted in the development of strong cystitis that persisted significantly longer than in mice challenged with bacterial suspensions alone but also required prolonged antibiotic treatment to reduce the level of infection. Treatment of infected mice for 4 days with ciprofloxacin at 30 mg/kg of body weight twice a day cured cystitis and renal infection in noncatheterized mice. Similarly, ciprofloxacin reduced the bacterial burden to undetectable levels in catheterized mice but did not inhibit rebound of the infection upon cessation of antibiotic therapy. This methodology easily allows spatial information to be monitored sequentially throughout the entire disease process, including ascending UTI, treatment efficacy, and relapse, all without exogenous sampling, which is not possible with conventional methods.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15972473
      14. Call Number :
        139333
      15. Serial :
        7110
      1. Author :
        Kadurugamuwa, J. L.; Modi, K.; Yu, J.; Francis, K. P.; Orihuela, C.; Tuomanen, E.; Purchio, A. F.; Contag, P. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Mol Imaging
      6. Products :
      7. Volume :
        4
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Diagnostic Imaging, Disease Models, Animal, Female, Luminescent Measurements/methods, Meningitis, Pneumococcal/drug therapy/microbiology/ radiography, Mice, Mice, Inbred BALB C, Streptococcus pneumoniae/drug effects IVIS, Xenogen, Xen10
      12. Abstract :
        Noninvasive real-time in vivo bioluminescent imaging was used to assess the spread of Streptococcus pneumoniae throughout the spinal cord and brain during the acute stages of bacterial meningitis. A mouse model was established by lumbar (LP) or intracisternal (IC) injection of bioluminescent S. pneumoniae into the subarachnoid space. Bacteria replicated initially at the site of inoculation and spread progressively from the spinal cord to the brain or from the brain down to the cervical part of the spinal column and to the lower vertebral levels. After 24 hr, animals showed strong bioluminescent signals throughout the spinal canal, indicating acute meningitis of the intracranial and intraspinal meninges. A decline in bacterial cell viability, as judged by a reduction in the bioluminescent signal, was observed over time in animals treated with ceftriaxone, but not in untreated groups. Mice treated with the antibiotic survived infection, whereas all mice in untreated groups became moribund, first in the IC group then in the LP group. No untreated animal survived beyond 48 hr after induction of infection. Colony counts of infected cerebrospinal fluid (CSF) correlated positively with bioluminescent signals. This methodology is especially appealing because it allows detecting infected mice as early as 3 hr after inoculation, provide temporal, sequential, and spatial distribution of bacteria within the brain and spinal cord throughout the entire disease process and the rapid monitoring of treatment efficacy in a nondestructive manner. Moreover, it avoids the need to sacrifice the animals for CSF sampling and the potential manipulative damage that can occur with other conventional methods.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16105511
      14. Call Number :
        139330
      15. Serial :
        7143
      1. Author :
        Kadurugamuwa, J. L.; Modi, K.; Coquoz, O.; Rice, B.; Smith, S.; Contag, P. R.; Purchio, T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        We developed a method for simultaneous in vivo biophotonic monitoring of pneumococcal meningitis and the accompanying neuronal injury in live transgenic mice. Streptococcus pneumoniae engineered for bioluminescence (lux) was used for direct visualization of disease progression and antibiotic treatment in a mouse model of meningitis. The host response was monitored in transgenic mice containing an inducible firefly luciferase (luc) reporter gene under transcriptional control of the mouse glial fibrillary acidic protein (GFAP) promoter. Based on the different spectra of light emission and substrate requirements for lux and luc, we were able to separately monitor the two reporters using a highly sensitive in vivo imaging system. The level of neuronal damage and recovery following antibiotic treatment was dependent on the time of treatment. This model has potential for simultaneous multiparameter monitoring and testing of therapies that target the pathogen or host response to prevent neuronal injury and recovery.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16299273
      14. Call Number :
        139327
      15. Serial :
        7497
      1. Author :
        Srivastava, Amit; Henneke, Philipp; Visintin, Alberto; Morse, Sarah C; Martin, Victoria; Watkins, Claire; Paton, James C; Wessels, Michael R; Golenbock, Douglas T; Malley, Richard
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        10
      9. Page Numbers :
        6479-6487
      10. Research Area :
        N/A
      11. Keywords :
        Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Bacterial Proteins; Caspases; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred Strains; Nasopharynx; Pneumococcal Infections; Streptococcus pneumoniae; Streptolysins; Xen10
      12. Abstract :
        Pneumolysin, the cholesterol-dependent cytolysin of Streptococcus pneumoniae, induces inflammatory and apoptotic events in mammalian cells. Toll-like receptor 4 (TLR4) confers resistance to pneumococcal infection via its interaction with pneumolysin, but the underlying mechanisms remain to be identified. In the present study, we found that pneumolysin-induced apoptosis is also mediated by TLR4 and confers protection against invasive disease. The interaction between TLR4 and pneumolysin is direct and specific; ligand-binding studies demonstrated that pneumolysin binds to TLR4 but not to TLR2. Involvement of TLR4 in pneumolysin-induced apoptosis was demonstrated in several complementary experiments. First, macrophages from wild-type mice were significantly more prone to pneumolysin-induced apoptosis than cells from TLR4-defective mice. In gain-of-function experiments, we found that epithelial cells expressing TLR4 and stimulated with pneumolysin were more likely to undergo apoptosis than cells expressing TLR2. A specific TLR4 antagonist, B1287, reduced pneumolysin-mediated apoptosis in wild-type cells. This apoptotic response was also partially caspase dependent as preincubation of cells with the pan-caspase inhibitor zVAD-fmk reduced pneumolysin-induced apoptosis. Finally, in a mouse model of pneumococcal infection, pneumolysin-producing pneumococci elicited significantly more upper respiratory tract cell apoptosis in wild-type mice than in TLR4-defective mice, and blocking apoptosis by administration of zVAD-fmk to wild-type mice resulted in a significant increase in mortality following nasopharyngeal pneumococcal exposure. Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16177320
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        10001