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Article: Applications of bioluminescence imaging to the study of infectious diseases.

Hutchens, Martha / Luker, Gary D

2007 Volume 9, Issue 10, Page(s) 2315–2322

Abstract: Bioluminescence imaging (BLI) has emerged as a powerful new method to analyse infectious diseases in animal models. BLI offers real-time monitoring of spatial and temporal progression of infection in the same animal, as opposed to euthanizing a cohort of ...

Abstract	Bioluminescence imaging (BLI) has emerged as a powerful new method to analyse infectious diseases in animal models. BLI offers real-time monitoring of spatial and temporal progression of infection in the same animal, as opposed to euthanizing a cohort of animals and quantifying colony or plaque forming units at multiple time points. Pathogens or mice are engineered to express genetically encoded luciferase enzymes from bacteria, insects, or the sea pansy. The seminal study showing the feasibility of detecting microbially generated luminescence within a living mouse was published by Contag and colleagues in 1995, using Salmonella typhimurium transformed with the lux operon from Photorhabdus luminescens. Following this, they and others performed many studies of infection by bioluminescent Gram-negative and Gram-positive bacteria. Viruses can also be engineered to encode luciferase. Our laboratory has used bioluminescent reporter viruses to follow HSV and vaccinia pathogenesis; others have used an alphavirus or novirhabdovirus. Recently, even eukaryotic parasites Plasmodium, Leishmania and Toxoplasma have been transformed with luciferase and yielded unique insights into their in vivo behaviour. We expect that both the range of organisms and the molecular events able to be studied by BLI will continue to expand, yielding important insights into mechanisms of pathogenesis.
MeSH term(s)	Animals ; Communicable Diseases/metabolism ; Communicable Diseases/microbiology ; Genes, Reporter ; Gram-Positive Bacteria/genetics ; Leishmania/genetics ; Luciferases/biosynthesis ; Luciferases/genetics ; Luminescent Measurements/instrumentation ; Luminescent Measurements/methods ; Mice ; Microbiological Techniques ; Mycoses/metabolism ; Mycoses/microbiology ; Parasitic Diseases/metabolism ; Parasitic Diseases/parasitology ; Plasmodium/genetics ; Toxoplasma/genetics ; Virus Diseases/metabolism ; Virus Diseases/virology ; Viruses/genetics
Chemical Substances	Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2007-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/j.1462-5822.2007.00995.x
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Article: Applications of bioluminescence imaging to the study of infectious diseases

Hutchens, Martha / Luker, Gary D

Cellular microbiology. 2007 Oct., v. 9, no. 10

2007

Abstract	Bioluminescence imaging (BLI) has emerged as a powerful new method to analyse infectious diseases in animal models. BLI offers real-time monitoring of spatial and temporal progression of infection in the same animal, as opposed to euthanizing a cohort of animals and quantifying colony or plaque forming units at multiple time points. Pathogens or mice are engineered to express genetically encoded luciferase enzymes from bacteria, insects, or the sea pansy. The seminal study showing the feasibility of detecting microbially generated luminescence within a living mouse was published by Contag and colleagues in 1995, using Salmonella typhimurium transformed with the lux operon from Photorhabdus luminescens. Following this, they and others performed many studies of infection by bioluminescent Gram-negative and Gram-positive bacteria. Viruses can also be engineered to encode luciferase. Our laboratory has used bioluminescent reporter viruses to follow HSV and vaccinia pathogenesis; others have used an alphavirus or novirhabdovirus. Recently, even eukaryotic parasites Plasmodium, Leishmania and Toxoplasma have been transformed with luciferase and yielded unique insights into their in vivo behaviour. We expect that both the range of organisms and the molecular events able to be studied by BLI will continue to expand, yielding important insights into mechanisms of pathogenesis.
Language	English
Dates of publication	2007-10
Size	p. 2315-2322.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/j.1462-5822.2007.00995.x
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation.

DiGiandomenico, Antonio / Veach, Ruth Ann / Zienkiewicz, Jozef / Moore, Daniel J / Wylezinski, Lukasz S / Hutchens, Martha A / Hawiger, Jacek

PloS one

2014 Volume 9, Issue 10, Page(s) e110183

Abstract: Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive ... ...

Abstract	Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide attenuates the systemic inflammatory response associated with lethal shock as well as localized lung inflammation.
MeSH term(s)	Active Transport, Cell Nucleus/drug effects ; Animals ; Bone Marrow Cells/cytology ; Cell Nucleus/drug effects ; Cell Nucleus/metabolism ; Cell-Penetrating Peptides/pharmacology ; Cell-Penetrating Peptides/therapeutic use ; Chemokines/blood ; Gene Expression Regulation/drug effects ; Genome, Human/drug effects ; Genome, Human/genetics ; Humans ; Lipopolysaccharides/toxicity ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Pneumonia/chemically induced ; Pneumonia/drug therapy ; Pneumonia/genetics ; Pneumonia/pathology ; Shock, Septic/chemically induced ; Shock, Septic/drug therapy ; Shock, Septic/genetics ; Shock, Septic/pathology ; Transcription Factors/metabolism ; Transcriptome/drug effects
Chemical Substances	Cell-Penetrating Peptides ; Chemokines ; Lipopolysaccharides ; Transcription Factors
Language	English
Publishing date	2014-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0110183
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Article ; Online: The "genomic storm" induced by bacterial endotoxin is calmed by a nuclear transport modifier that attenuates localized and systemic inflammation.

Antonio DiGiandomenico / Ruth Ann Veach / Jozef Zienkiewicz / Daniel J Moore / Lukasz S Wylezinski / Martha A Hutchens / Jacek Hawiger

PLoS ONE, Vol 9, Iss 10, p e

2014 Volume 110183

Abstract	Lipopolysaccharide (LPS) is a potent microbial virulence factor that can trigger production of proinflammatory mediators involved in the pathogenesis of localized and systemic inflammation. Importantly, the role of nuclear transport of stress responsive transcription factors in this LPS-generated "genomic storm" remains largely undefined. We developed a new nuclear transport modifier (NTM) peptide, cell-penetrating cSN50.1, which targets nuclear transport shuttles importin α5 and importin β1, to analyze its effect in LPS-induced localized (acute lung injury) and systemic (lethal endotoxic shock) murine inflammation models. We analyzed a human genome database to match 46 genes that encode cytokines, chemokines and their receptors with transcription factors whose nuclear transport is known to be modulated by NTM. We then tested the effect of cSN50.1 peptide on proinflammatory gene expression in murine bone marrow-derived macrophages stimulated with LPS. This NTM suppressed a proinflammatory transcriptome of 37 out of 84 genes analyzed, without altering expression of housekeeping genes or being cytotoxic. Consistent with gene expression analysis in primary macrophages, plasma levels of 23 out of 26 LPS-induced proinflammatory cytokines, chemokines, and growth factors were significantly attenuated in a murine model of LPS-induced systemic inflammation (lethal endotoxic shock) while the anti-inflammatory cytokine, interleukin 10, was enhanced. This anti-inflammatory reprogramming of the endotoxin-induced genomic response was accompanied by complete protection against lethal endotoxic shock with prophylactic NTM treatment, and 75% protection when NTM was first administered after LPS exposure. In a murine model of localized lung inflammation caused by direct airway exposure to LPS, expression of cytokines and chemokines in the bronchoalveolar space was suppressed with a concomitant reduction of neutrophil trafficking. Thus, calming the LPS-triggered "genomic storm" by modulating nuclear transport with cSN50.1 peptide ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection.

Hutchens, Martha A / Luker, Kathryn E / Sonstein, Joanne / Núñez, Gabriel / Curtis, Jeffrey L / Luker, Gary D

PLoS pathogens

2008 Volume 4, Issue 9, Page(s) e1000153

Abstract: Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between ...

Abstract	Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between these viruses and their hosts. We recently determined that TLR3 regulates a detrimental innate immune response that enhances replication, morbidity, and mortality in mice in response to vaccinia virus, a model pathogen for studies of poxviruses. To further investigate Toll-like receptor signaling in vaccinia infection, we first focused on TRIF, the only known adapter protein for TLR3. Unexpectedly, bioluminescence imaging showed that mice lacking TRIF are more susceptible to vaccinia infection than wild-type mice. We then focused on TLR4, the other Toll-like receptor that signals through TRIF. Following respiratory infection with vaccinia, mice lacking TLR4 signaling had greater viral replication, hypothermia, and mortality than control animals. The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung. Challenge of primary bone marrow macrophages isolated from TLR4 mutant and control mice suggested that TLR4 recognizes a viral ligand rather than an endogenous ligand. These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.
MeSH term(s)	Adaptor Proteins, Vesicular Transport/deficiency ; Adaptor Proteins, Vesicular Transport/immunology ; Animals ; Cells, Cultured ; Immunity, Innate ; Lung Diseases/immunology ; Lung Diseases/virology ; Macrophages/immunology ; Macrophages/virology ; Mice ; Mice, Knockout ; Toll-Like Receptor 4/deficiency ; Toll-Like Receptor 4/immunology ; Vaccinia/immunology ; Vaccinia virus/immunology
Chemical Substances	Adaptor Proteins, Vesicular Transport ; TICAM-1 protein, mouse ; Tlr4 protein, mouse ; Toll-Like Receptor 4
Language	English
Publishing date	2008-09-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1000153
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Murine alveolar macrophages limit replication of vaccinia virus.

Rivera, Rachel / Hutchens, Martha / Luker, Kathryn E / Sonstein, Joanne / Curtis, Jeffrey L / Luker, Gary D

Virology

2007 Volume 363, Issue 1, Page(s) 48–58

Abstract: Because of concerns about zoonotic transmission of monkeypox to humans and the bioterrorism threat posed by orthopoxviruses, there is renewed interest in probing cellular and molecular mechanisms of host defense to these pathogens. In particular, it is ... ...

Abstract	Because of concerns about zoonotic transmission of monkeypox to humans and the bioterrorism threat posed by orthopoxviruses, there is renewed interest in probing cellular and molecular mechanisms of host defense to these pathogens. In particular, it is essential to understand viral-host interactions in the respiratory tract, which is the route of infection for smallpox and a likely route of transmission for monkeypox. In this study, we analyze functions of alveolar macrophages in poxvirus infection, using a recombinant vaccinia virus expressing firefly luciferase to quantify infection in mice and cell culture. Depletion of alveolar macrophages with liposomal clodronate worsens the overall severity of infection in mice, including greater replication and systemic dissemination of vaccinia as determined by bioluminescence imaging. Absence of alveolar macrophages increases total numbers of granulocytes and granulocytes/monocyte progenitor cells in the lungs during vaccinia infection, indicating that protective effects of alveolar macrophages may be mediated in part by reducing the host inflammation. Alveolar macrophages also limit vaccinia infection in respiratory epithelium, as shown by a co-culture model of cell lines derived from alveolar macrophages and lung epithelium. Collectively, these data demonstrate that alveolar macrophages are key determinants of host defense against local and systemic infection with poxviruses.
MeSH term(s)	Animals ; Clodronic Acid/pharmacology ; Coculture Techniques ; Leukocytes/immunology ; Lung/cytology ; Lung/immunology ; Macrophages, Alveolar/cytology ; Macrophages, Alveolar/immunology ; Mice ; Mice, Inbred BALB C ; Rats ; Respiratory Mucosa/cytology ; Respiratory Mucosa/immunology ; Vaccinia/immunology ; Vaccinia/virology ; Vaccinia virus/immunology ; Vaccinia virus/physiology ; Virus Replication
Chemical Substances	Clodronic Acid (0813BZ6866)
Language	English
Publishing date	2007-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2007.01.033
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Bioluminescence imaging of vaccinia virus: effects of interferon on viral replication and spread.

Luker, Kathryn E / Hutchens, Martha / Schultz, Tracey / Pekosz, Andrew / Luker, Gary D

Virology

2005 Volume 341, Issue 2, Page(s) 284–300

Abstract: Whole animal imaging allows viral replication and localization to be monitored in intact animals, which provides significant advantages for determining viral and host factors that determine pathogenesis. To investigate effects of interferons on spatial ... ...

Abstract	Whole animal imaging allows viral replication and localization to be monitored in intact animals, which provides significant advantages for determining viral and host factors that determine pathogenesis. To investigate effects of interferons on spatial and temporal progression of vaccinia infection, we generated recombinant viruses that express firefly luciferase or a monomeric orange fluorescent protein. These viruses allow vaccinia infection to be monitored with bioluminescence or fluorescence imaging, respectively. The recombinant viruses were not attenuated in vitro or in vivo relative to a control WR virus. In cell culture, reporters could be detected readily by 4 h post-infection, showing that these viruses can be used as early markers of infection. The magnitude of firefly luciferase activity measured with bioluminescence imaging in vitro and in vivo correlated directly with increasing titers of vaccinia virus, validating imaging data as a marker of viral infection. Replication of vaccinia was significantly greater in mice lacking receptors for type I interferons (IFN I R-/-) compared with wild-type mice, although both genotypes of mice developed focal infections in lungs and brain after intranasal inoculation. IFN I R-/- mice had greater dissemination of virus to liver and spleen than wild-type animals even when mortality occurred at the same time point after infection. Protective effects of type I interferons were mediated primarily through parenchymal cells rather than hematopoietic cells as analyzed by bone marrow transplant experiments. Collectively, our data define a new function for type I interferon signaling in systemic dissemination of vaccinia and validate these reporter viruses for studies of pathogenesis.
MeSH term(s)	Animals ; Brain/virology ; Cercopithecus aethiops ; Diagnostic Imaging ; Disease Models, Animal ; Female ; Genes, Reporter ; Interferons/physiology ; Liver/virology ; Luciferases, Firefly/genetics ; Luciferases, Firefly/metabolism ; Luminescent Measurements ; Lung/virology ; Male ; Mice ; Mice, Knockout ; Receptors, Interferon/genetics ; Receptors, Interferon/physiology ; Spleen/virology ; Staining and Labeling ; Vaccinia/pathology ; Vaccinia/virology ; Vaccinia virus/genetics ; Vaccinia virus/physiology ; Vero Cells ; Viral Plaque Assay ; Virus Replication
Chemical Substances	Receptors, Interferon ; interferon receptor, type II ; Interferons (9008-11-1) ; Luciferases, Firefly (EC 1.13.12.7)
Language	English
Publishing date	2005-10-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2005.06.049
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Article: TLR3 increases disease morbidity and mortality from vaccinia infection.

Hutchens, Martha / Luker, Kathryn E / Sottile, Peter / Sonstein, Joanne / Lukacs, Nicholas W / Núñez, Gabriel / Curtis, Jeffrey L / Luker, Gary D

Journal of immunology (Baltimore, Md. : 1950)

2007 Volume 180, Issue 1, Page(s) 483–491

Abstract: Innate immunity is required for effective control of poxvirus infections, but cellular receptors that initiate the host response to these DNA viruses remain poorly defined. Given this information and the fact that functions of TLRs in immunity to DNA ... ...

Abstract	Innate immunity is required for effective control of poxvirus infections, but cellular receptors that initiate the host response to these DNA viruses remain poorly defined. Given this information and the fact that functions of TLRs in immunity to DNA viruses remain controversial, we investigated effects of TLR3 on pathogenesis of vaccinia virus, a prototype poxvirus. We used a recombinant strain Western Reserve vaccinia virus that expresses firefly luciferase to infect wild-type C57BL/6 and TLR3-/- mice through intranasal inoculation. Bioluminescence imaging showed that TLR3-/- mice had substantially lower viral replication in the respiratory tract and diminished dissemination of virus to abdominal organs. Mice lacking TLR3 had reduced disease morbidity, as measured by decreased weight loss and hypothermia after infection. Importantly, TLR3-/- mice also had improved survival relative to wild-type mice. Infected TLR3-/- mice had significantly reduced lung inflammation and recruitment of leukocytes to the lung. Mice lacking TLR3 also had lower levels of inflammatory cytokines, including IL-6, MCP-1, and TNF-alpha in serum and/or bronchoalveolar lavage fluid, but levels of IFN-beta did not differ between genotypes of mice. To our knowledge, our findings show for the first time that interactions between TLR3 and vaccinia increase viral replication and contribute to detrimental effects of the host immune response to poxviruses.
MeSH term(s)	Animals ; Cytokines/metabolism ; Female ; Luciferases/analysis ; Luciferases/genetics ; Lung/immunology ; Lung/pathology ; Lung/virology ; Male ; Mice ; Mice, Knockout ; Toll-Like Receptor 3/genetics ; Toll-Like Receptor 3/physiology ; Vaccinia/immunology ; Vaccinia/pathology ; Vaccinia/virology ; Vaccinia virus/genetics ; Vaccinia virus/physiology ; Virus Replication
Chemical Substances	Cytokines ; TLR3 protein, mouse ; Toll-Like Receptor 3 ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2007-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.180.1.483
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Article ; Online: Protective effect of Toll-like receptor 4 in pulmonary vaccinia infection.

Martha A Hutchens / Kathryn E Luker / Joanne Sonstein / Gabriel Núñez / Jeffrey L Curtis / Gary D Luker

PLoS Pathogens, Vol 4, Iss 9, p e

2008 Volume 1000153

Abstract	Innate immune responses are essential for controlling poxvirus infection. The threat of a bioterrorist attack using Variola major, the smallpox virus, or zoonotic transmission of other poxviruses has renewed interest in understanding interactions between these viruses and their hosts. We recently determined that TLR3 regulates a detrimental innate immune response that enhances replication, morbidity, and mortality in mice in response to vaccinia virus, a model pathogen for studies of poxviruses. To further investigate Toll-like receptor signaling in vaccinia infection, we first focused on TRIF, the only known adapter protein for TLR3. Unexpectedly, bioluminescence imaging showed that mice lacking TRIF are more susceptible to vaccinia infection than wild-type mice. We then focused on TLR4, the other Toll-like receptor that signals through TRIF. Following respiratory infection with vaccinia, mice lacking TLR4 signaling had greater viral replication, hypothermia, and mortality than control animals. The mechanism of TLR4-mediated protection was not due to increased release of proinflammatory cytokines or changes in total numbers of immune cells recruited to the lung. Challenge of primary bone marrow macrophages isolated from TLR4 mutant and control mice suggested that TLR4 recognizes a viral ligand rather than an endogenous ligand. These data establish that TLR4 mediates a protective innate immune response against vaccinia virus, which informs development of new vaccines and therapeutic agents targeted against poxviruses.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2008-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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