1.In vivo characterization of the integrin beta3 as a receptor for Hantaan virus cellular entry.
Jin Won SONG ; Ki Joon SONG ; Luck Ju BAEK ; Blasie FROST ; Mortimer PONCZ ; Kwang Sook PARK
Experimental & Molecular Medicine 2005;37(2):121-127
Binding of viruses to cell surface molecules is an essential step in viral infection. In vitro studies suggested that the alpha v beta3 integrin receptor is the epithelial cell receptor for Hantaan virus (HTNV). Whether beta3 is in vivo the only or central cellular receptor for HTNV infection is not known. To investigate the role of beta3 integrin for cellular entry of HTNV, we established an HTNV infection model in newborn murine pups. Infected pups died at an average age of 14.2 +/- 1.1 days with high levels of viral antigen detected in their brain, lung, and kidney. Pre-injection of blocking monoclonal antibodies (mAb) specific for either beta3 or av prolonged survival significantly to a maximal average survival of 19.7 +/- 1.5 days (P<0.01) and 18.4 +/- 0.9 days (P<0.01), respectively. XT-199, a chemical blocker of the alpha v beta3 receptor also prolonged survival to 19.5 +/- 1.3 days (P<0.01). In contrast to these receptor blockades, anti-HTNV antibody was not only able to prolong survival, but 20% of infected pups achieved long-term survival. An anti-murine beta1 antibody comparatively prolonged survival (19.0 +/- 1.2 days), suggesting that HTNV infection is partly mediated through integrin beta1 receptors as well as through beta3 receptors in vivo. Our data demonstrate that the beta3 receptor is important for HTNV infection in vivo, but also suggest that HTNV may utilize additional receptors beyond beta3 for cellular entry within an organism.
Animals
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Animals, Newborn
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Antibodies, Monoclonal/therapeutic use
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Antigens, CD29/metabolism
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Hantaan virus/*metabolism/pathogenicity
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Hemorrhagic Fever with Renal Syndrome/mortality/*virology
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Imidazoles/pharmacology
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Integrin alphaV/metabolism
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Integrin alphaVbeta3/antagonists & inhibitors
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Integrin beta3/*metabolism
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Mice
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Receptors, Virus/*metabolism
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
2.Expression of ICAM-1 on the Hantaan virus-infected human umbilical vein endothelial cells.
Jeong Soo SONG ; Cheol Hong MIN ; Eungtaek KANG ; Suk Hee YU
The Korean Journal of Internal Medicine 1999;14(2):47-54
OBJECTIVES: In HFRS, there is a varying degree of disseminated intravascular coagulation which was evident in the early phase of the illness. It is believed also that DIC would be the consequence, at least in part, of functional changes of endothelium resulting in kinin activation and clinical syndrome. This study investigated the role of adhesion molecule in the pathogenesis of Hantaan virus-related disease. METHODS: The expression of ICAM-1 antigen on the cell membrane of human umbilical vein endothelial cells was assessed by immunohistochemistry, and ICAM-1 mRNA in the endothelial cells was assessed by in situ hybridization after Hantaan virus infection (2.6 x 10(4) PFU/mL) with the time course. RESULTS: In immunohistochemistry, the number of ICAM-1 positive cells increased with time during the 12 or 24 hours after infection. 5 to 10% of HUVECs had been positive after 12-24 hours and the number of positive cells decreased abruptly after 24 hours. Hantaan antigen had been noticed after 12 hours focally on the HUVECs but continued to proliferate into day 7 post-infection when most of HUVECs were infected by Hantaan virus. In situ hybridization showed identical patterns of ICAM-1 mRNA expression after Hantaan virus infection. CONCLUSION: It implies that the Hantaan virus infection on HUVECs would express more ICAM-1 on their surface and implicated in the pathogenesis of early clinical syndrome of HFRS.
Cell Line
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Endothelium, Vascular/virology
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Endothelium, Vascular/immunology
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Gene Expression
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Hantaan Virus/pathogenicity*
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Hemorrhagic Fever with Renal Syndrome/immunology*
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Hemorrhagic Fever with Renal Syndrome/genetics
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Hemorrhagic Fever with Renal Syndrome/etiology
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Human
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Immunohistochemistry
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In Situ Hybridization
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Intercellular Adhesion Molecule-1/metabolism*
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Intercellular Adhesion Molecule-1/genetics*
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RNA, Messenger/metabolism
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RNA, Messenger/genetics