Pathogenic hantaviruses selectively inhibit beta3 integrin directed endothelial cell migration.
Hantaviruses cause two diseases of man, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Pathogenic and non-pathogenic hantaviruses use beta3 and beta1 integrins, respectively, to enter endothelial cells. Beta3 integrins were recently reported to bind receptors that regulate vascular permeability suggesting that hantavirus beta3 integrin interactions may regulate endothelial cell function and contribute to viral pathogenesis. In this study we investigated the ability of pathogenic and non-pathogenic hantaviruses to regulate beta3 and beta1 integrin directed endothelial cell functions. We found that pathogenic NY-1, SNV, HTN, SEO and PUU viruses blocked endothelial cell migration on beta3, but not beta1, integrin ligands. Migration is similarly inhibited by antibodies to beta3 integrins which selectively block vitronectin directed endothelial cell migration. As a result, the ability of endothelial cells to migrate on integrin ligands was selectively inhibited by only pathogenic hantaviruses. Infection by NY-1 virus inhibited endothelial cell migration as early as 24-48 h post-infection. In contrast, non-pathogenic PH and TUL viruses had no effect on the ability of endothelial cells to migrate on either beta3 or beta1 integrin ligands from 1 to 5 days post-infection. These findings indicate that only hantaviruses which use beta3 integrins, and are associated with HPS and HFRS diseases, functionally dysregulate endothelial cell migration. These findings further demonstrate that hantaviruses regulate only beta3 integrin directed endothelial cell functions and have no effect on beta1 integrin functions. Since beta3 integrins are linked to changes in vascular permeability and the maintenance of vascular integrity, these findings suggest a means by which hantavirus usage and regulation of beta3 integrins may contribute to hantavirus pathogenesis.
Gavrilovskaya
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Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, USA.
Peresleni
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Geimonen
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Mackow
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D002465:Cell Movement; D004730:Endothelium, Vascular / Q000166:cytology*; D006476:Orthohantavirus / Q000472:pathogenicity*; D006801:Humans; D019012:Integrin beta1 / Q000032:analysis; D039661:Integrin beta3 / Q000032:analysis / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D019012:Integrin beta1; D039661:Integrin beta3; D040301:Vascular Endothelial Growth Factor Receptor-2