tetano
Editor, Senior Moderator
J Virol. 2010 Aug 11. [Epub ahead of print]
Toll Like Receptor 4 mediated p38 Mitogen Activated Protein Kinase Activation is a Determinant of Respiratory Virus Entry and Tropism.
Marchant D, Singhera GK, Utokaparch S, Hackett TL, Boyd JH, Luo Z, Si X, Dorscheid DR, McManus BM, Hegele RG.
UBC James Hogg Research Laboratories, Providence Heart + Lung Institute, Department of Pathology and Laboratory Medicine, University of British Columbia, Room 166-Burrard Building, St. Paul's Hospital, 1081 Burrard Street Vancouver, British Columbia, Canada, V6Z-1Y6.
Abstract
Respiratory viruses exert a heavy toll of morbidity and mortality worldwide. Despite this burden there are few specific treatments available for respiratory virus infections. Since many viruses utilize host cell enzymatic machinery such as protein kinases for replication, we determined whether pharmacological inhibition of kinases could, in principle, be used as a broad anti-viral strategy for common human respiratory virus infections. A panel of GFP-expressing recombinant respiratory viruses, including an isolate of H1N1 influenza (H1N1/Weiss/43) were used to represent a broad range of virus families, responsible for common respiratory infections (Adeno, Paramyxo, Picorna, and Orthomyxo). Kinase inhibitors were screened in a high-throughput assay that detected virus infection in human airway epithelial cells (1HAEo-) using a fluorescent plate reader. Inhibition of p38 MAP kinase signalling was able to significantly inhibit replication by all viruses tested. Therefore the pathways involved in virus mediated p38 and ERK Mitogen Activated Protein kinase (MAPKs) activation were investigated using bronchial epithelial cells and primary fibroblasts derived from MyD88 knock-out mouse lungs. Influenza, which activated p38 MAPK to approximately 10-fold greater levels than RSV in 1HAEo- cells was internalized about 8-fold faster and more completely than RSV. We show for the first time that p38 MAPK is a determinant of virus infection that is dependent upon MyD88 expression and TLR4 ligation. Imaging of virus TLR4 interactions showed significant clustering of TLR4 at the site of virus-cell interaction, triggering phosphorylation of downstream targets of p38 MAPK, suggesting the need for a signalling receptor to activate virus internalization.
PMID: 20702616 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20702616
Toll Like Receptor 4 mediated p38 Mitogen Activated Protein Kinase Activation is a Determinant of Respiratory Virus Entry and Tropism.
Marchant D, Singhera GK, Utokaparch S, Hackett TL, Boyd JH, Luo Z, Si X, Dorscheid DR, McManus BM, Hegele RG.
UBC James Hogg Research Laboratories, Providence Heart + Lung Institute, Department of Pathology and Laboratory Medicine, University of British Columbia, Room 166-Burrard Building, St. Paul's Hospital, 1081 Burrard Street Vancouver, British Columbia, Canada, V6Z-1Y6.
Abstract
Respiratory viruses exert a heavy toll of morbidity and mortality worldwide. Despite this burden there are few specific treatments available for respiratory virus infections. Since many viruses utilize host cell enzymatic machinery such as protein kinases for replication, we determined whether pharmacological inhibition of kinases could, in principle, be used as a broad anti-viral strategy for common human respiratory virus infections. A panel of GFP-expressing recombinant respiratory viruses, including an isolate of H1N1 influenza (H1N1/Weiss/43) were used to represent a broad range of virus families, responsible for common respiratory infections (Adeno, Paramyxo, Picorna, and Orthomyxo). Kinase inhibitors were screened in a high-throughput assay that detected virus infection in human airway epithelial cells (1HAEo-) using a fluorescent plate reader. Inhibition of p38 MAP kinase signalling was able to significantly inhibit replication by all viruses tested. Therefore the pathways involved in virus mediated p38 and ERK Mitogen Activated Protein kinase (MAPKs) activation were investigated using bronchial epithelial cells and primary fibroblasts derived from MyD88 knock-out mouse lungs. Influenza, which activated p38 MAPK to approximately 10-fold greater levels than RSV in 1HAEo- cells was internalized about 8-fold faster and more completely than RSV. We show for the first time that p38 MAPK is a determinant of virus infection that is dependent upon MyD88 expression and TLR4 ligation. Imaging of virus TLR4 interactions showed significant clustering of TLR4 at the site of virus-cell interaction, triggering phosphorylation of downstream targets of p38 MAPK, suggesting the need for a signalling receptor to activate virus internalization.
PMID: 20702616 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20702616