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      1. Author :
        Kirby, A. C.; Beattie, L.; Maroof, A.; Rooijen, N. van; Kaye, P. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        American Journal of Pathology
      6. Products :
      7. Volume :
        175
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        Marginal zone macrophages in the murine spleen play an important role in the capture of blood-borne pathogens and are viewed as an essential component of host defense against the development of pneumococcal sepsis. However, we and others have previously described the loss of marginal zone macrophages associated with the splenomegaly that follows a variety of viral and protozoal infections; this finding raises the question of whether these infected mice would become more susceptible to secondary pneumococcal infection. Contrary to expectations, we found that mice lacking marginal zone macrophages resulting from Leishmania donovani infection have increased resistance to Streptococcus pneumoniae type 3 and do not develop sepsis. Using biophotonic imaging, we observed that pneumococci are rapidly trapped in the spleens of L. donovani-infected mice. By selective depletion studies using clodronate liposomes, depleting monoclonal antibodies specific for Ly6C/G and Ly6G, and CD11c-DTR mice, we show that the enhanced early resistance in L. donovani-infected mice is entirely due to the activity of SIGNR1? red pulp macrophages. Our data demonstrate, therefore, that the normal requirement for SIGNR1+ marginal zone macrophages to protect against a primary pneumococcal infection can, under conditions of splenomegaly, be readily compensated for by activated red pulp macrophages.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19644016
      14. Call Number :
        139699
      15. Serial :
        7610
      1. Author :
        Wang, J.; Barke, R. A.; Charboneau, R.; Schwendener, R.; Roy, S.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        J Immunol
      6. Products :
      7. Volume :
        180
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Cell Line, Cell Line, Transformed, Humans, Macrophages, Alveolar/*drug effects/immunology/*microbiology/pathology, Mice, Mice, Inbred C57BL, Morphine/administration & dosage/*therapeutic use, NF-kappa B/*antagonists & inhibitors/physiology, Neutrophil Infiltration/drug effects/immunology, Pneumonia, Pneumococcal/*drug therapy/*immunology/microbiology/mortality, Signal Transduction/*drug effects/immunology, Streptococcus pneumoniae/drug effects/*immunology, Time Factors, Toll-Like Receptor 2/physiology, Toll-Like Receptor 4/physiology, Toll-Like Receptor 9/*antagonists & inhibitors/physiology IVIS, Xenogen, Xen10
      12. Abstract :
        Resident alveolar macrophages and respiratory epithelium constitutes the first line of defense against invading lung pneumococci. Results from our study showed that increased mortality and bacterial outgrowth and dissemination seen in morphine-treated mice were further exaggerated following depletion of alveolar macrophages with liposomal clodronate. Using an in vitro alveolar macrophages and lung epithelial cells infection model, we show significant release of MIP-2 from alveolar macrophages, but not from lung epithelial cells, following 4 h of exposure of cells to pneumococci infection. Morphine treatment reduced MIP-2 release in pneumococci stimulated alveolar macrophages. Furthermore, morphine treatment inhibited Streptococcus pneumoniae-induced NF-kappaB-dependent gene transcription in alveolar macrophages following 2 h of in vitro infection. S. pneumoniae infection resulted in a significant induction of NF-kappaB activity only in TLR9 stably transfected HEK 293 cells, but not in TLR2 and TLR4 transfected HEK 293 cells, and morphine treatment inhibited S. pneumoniae-induced NF-kappaB activity in these cells. Moreover, morphine treatment also decreased bacterial uptake and killing in alveolar macrophages. Taken together, these results suggest that morphine treatment impairs TLR9-NF-kappaB signaling and diminishes bacterial clearance following S. pneumoniae infection in resident macrophages during the early stages of infection, leading to a compromised innate immune response.
      13. URL :
        http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18292587
      14. Call Number :
        144073
      15. Serial :
        6976
      1. Author :
        Ogunniyi, A. D.; Paton, J. C.; Kirby, A. C.; McCullers, J. A.; Cook, J.; Hyodo, M.; Hayakawa, Y.; Karaolis, D. K.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Vaccine
      6. Products :
      7. Volume :
        26
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        Cyclic diguanylate (c-di-GMP) is a unique bacterial intracellular signaling molecule capable of stimulating enhanced protective innate immunity against various bacterial infections. The effects of intranasal pretreatment with c-di-GMP, or intraperitoneal coadministration of c-di-GMP with the pneumolysin toxoid (PdB) or pneumococcal surface protein A (PspA) before pneumococcal challenge, were investigated in mice. We found that c-di-GMP had no significant direct short-term effect on the growth rate of Streptococcus pneumoniae either in vitro or in vivo. However, intranasal pretreatment of mice with c-di-GMP resulted in a significant decrease in bacterial load in lungs and blood after serotypes 2 and 3 challenge, and a significant decrease in lung titers after serotype 4 challenge. Potential cellular mediators of these enhanced protective responses were identified in lungs and draining lymph nodes. Intraperitoneal coadministration of c-di-GMP with PdB or PspA before challenge resulted in significantly higher antigen-specific antibody titers and increased survival of mice, compared to that obtained with alum adjuvant. These findings demonstrate that local or systemic c-di-GMP administration stimulates innate and adaptive immunity against invasive pneumococcal disease. We propose that c-di-GMP can be used as an effective broad spectrum immunomodulator and vaccine adjuvant to prevent infectious diseases.
      13. URL :
        http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18640167
      14. Call Number :
        141772
      15. Serial :
        5663
      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 :
        Malley, R.; Henneke, P.; Morse, S. C.; Cieslewicz, M. J.; Lipsitch, M.; Thompson, C. M.; Kurt-Jones, E.; Paton, J. C.; Wessels, M. R.; Golenbock, D. T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2003
      5. Publication :
        Proceedings of the National Academy of Sciences of the United States of America
      6. Products :
      7. Volume :
        100
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen10
      12. Abstract :
        Streptococcus pneumoniae is one of the leading causes of invasive bacterial disease worldwide. Fragments of the cell wall and the cytolytic toxin pneumolysin have been shown to contribute substantially to inflammatory damage, although the interactions between pneumococcal components and host-cell structures have not been elucidated completely. Results of a previous study indicated that cell-wall components of pneumococci are recognized by Toll-like receptor (TLR)2 but suggested that pneumolysin induces inflammatory events independently of this receptor. In this study we tested the hypothesis that pneumolysin interacts with surface proteins of the TLR family other than TLR2. We found that pneumolysin stimulates tumor necrosis factor-? and IL-6 release in wild-type macrophages but not in macrophages from mice with a targeted deletion of the cytoplasmic TLR-adapter molecule myeloid differentiation factor 88, suggesting the involvement of the TLRs in pneumolysin recognition. Purified pneumolysin synergistically activated macrophage responses together with preparations of pneumococcal cell walls or staphylococcal peptidoglycan, which are known to activate TLR2. Furthermore, when compared with wild-type macrophages, macrophages from mice that carry a spontaneous mutation in TLR4 (P712H) were hyporesponsive to both pneumolysin alone and the combination of pneumolysin with pneumococcal cell walls. Finally, these TLR4-mutant mice were significantly more susceptible to lethal infection after intranasal colonization with pneumolysin-positive pneumococci than were control mice. We conclude that the interaction of pneumolysin with TLR4 is critically involved in the innate immune response to pneumococcus.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/12569171
      14. Call Number :
        140854
      15. Serial :
        7487
      1. Author :
        Echchannaoui, H.; Frei, K.; Schnell, C.; Leib, S. L.; Zimmerli, W.; Landmann, R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2002
      5. Publication :
        Journal of Infectious Diseases
      6. Products :
      7. Volume :
        186
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, Ceftriaxone/therapeutic use, Cephalosporins/therapeutic use, Disease Models, Animal, Disease Susceptibility, Drosophila Proteins, Inflammation/genetics/immunology/microbiology/pathology, Listeria Infections/genetics/immunology, Listeria monocytogenes/genetics/immunology, Membrane Glycoproteins/ deficiency/genetics, Meningitis, Bacterial/ genetics/ immunology/microbiology/pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumococcal Infections/genetics/immunology/microbiology/pathology, Receptors, Cell Surface/ deficiency/genetics, Streptococcus pneumoniae/ immunology, Time Factors, Toll-Like Receptor 2, Toll-Like Receptors IVIS, Xenogen, Xen10
      12. Abstract :
        Toll-like receptor-2 (TLR2) mediates host responses to gram-positive bacterial wall components. TLR2 function was investigated in a murine Streptococcus pneumoniae meningitis model in wild-type (wt) and TLR2-deficient (TLR2(-/-)) mice. TLR2(-/-) mice showed earlier time of death than wt mice (P<.02). Plasma interleukin-6 levels and bacterial numbers in blood and peripheral organs were similar for both strains. With ceftriaxone therapy, none of the wt but 27% of the TLR2(-/-) mice died (P<.04). Beyond 3 hours after infection, TLR2(-/-) mice had higher bacterial loads in brain than did wt mice, as assessed with luciferase-tagged S. pneumoniae by means of a Xenogen-CCD (charge-coupled device) camera. After 24 h, tumor necrosis factor activity was higher in cerebrospinal fluid of TLR2(-/-) than wt mice (P<.05) and was related to increased blood-brain barrier permeability (Evans blue staining, P<.02). In conclusion, the lack of TLR2 was associated with earlier death from meningitis, which was not due to sepsis but to reduced brain bacterial clearing, followed by increased intrathecal inflammation.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/12198614
      14. Call Number :
        137638
      15. Serial :
        7950
      1. Author :
        Mann, B.; Orihuela, C.; Antikainen, J.; Gao, G.; Sublett, J.; Korhonen, T. K.; Tuomanen, E.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2006
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        74
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen7
      12. Abstract :
        Members of the choline binding protein (Cbp) family are noncovalently bound to phosphorylcholine residues on the surface of Streptococcus pneumoniae. It has been suggested that CbpG plays a role in adherence and increase virulence both at the mucosal surface and in the bloodstream, but the function of this protein has been unclear. A new sequence analysis indicated that CbpG is a possible member of the S1 family of multifunctional surface-associated serine proteases. Clinical isolates contained two alleles of cbpG, and one-third of the strains expressed a truncated protein lacking the C-terminal, cell wall-anchoring choline binding domain. CbpG on the surface of pneumococci (full length) or released into the supernatant (truncated) showed proteolytic activity for fibronectin and casein, as did CbpG expressed on lactobacilli or as a purified full-length or truncated recombinant protein. Recombinant CbpG (rCbpG)-coated beads adhered to eukaryotic cells, and TIGR4 mutants lacking CbpG or having a truncated CbpG protein showed decreased adherence in vitro and attenuation of disease in mouse challenge models of colonization, pneumonia, and bacteremia. Immunization with rCbpG was protective in an animal model of colonization and sepsis. We propose that CbpG is a multifunctional surface protein that in the cell-attached or secreted form cleaves host extracellular matrix and in the cell-attached form participates in bacterial adherence. This is the first example of distinct functions in virulence that are dependent on natural variation in expression of a choline binding domain.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16428724
      14. Call Number :
        140887
      15. Serial :
        6992
      1. Author :
        Orihuela, C. J.; Radin, J. N.; Sublett, J. E.; Gao, G.; Kaushal, D.; Tuomanen, E. I.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2004
      5. Publication :
        Infection and Immunity
      6. Products :
      7. Volume :
        72
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, Xenogen, Xen7, Xen35
      12. Abstract :
        Streptococcus pneumoniae is a leading cause of invasive bacterial disease. This is the first study to examine the expression of S. pneumoniae genes in vivo by using whole-genome microarrays available from The Institute for Genomic Research. Total RNA was collected from pneumococci isolated from infected blood, infected cerebrospinal fluid, and bacteria attached to a pharyngeal epithelial cell line in vitro. Microarray analysis of pneumococcal genes expressed in these models identified body site-specific patterns of expression for virulence factors, transporters, transcription factors, translation-associated proteins, metabolism, and genes with unknown function. Contributions to virulence predicted for several unknown genes with enhanced expression in vivo were confirmed by insertion duplication mutagenesis and challenge of mice with the mutants. Finally, we cross-referenced our results with previous studies that used signature-tagged mutagenesis and differential fluorescence induction to identify genes that are potentially required by a broad range of pneumococcal strains for invasive disease.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/15385455
      14. Call Number :
        141856
      15. Serial :
        6874