, Volume 147, Issue 10, pp 1913-1931

Pathogenic hantaviruses selectively inhibit β3 integrin directed endothelial cell migration

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 Hantaviruses cause two diseases of man, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Pathogenic and non-pathogenic hantaviruses use β3 and β1 integrins, respectively, to enter endothelial cells. β3 integrins were recently reported to bind receptors that regulate vascular permeability suggesting that hantavirus β3 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 β3 and β1 integrin directed endothelial cell functions. We found that pathogenic NY-1, SNV, HTN, SEO and PUU viruses blocked endothelial cell migration on β3, but not β1, integrin ligands. Migration is similarly inhibited by antibodies to β3 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 β3 or β1 integrin ligands from 1 to 5 days post-infection. These findings indicate that only hantaviruses which use β3 integrins, and are associated with HPS and HFRS diseases, functionally dysregulate endothelial cell migration. These findings further demonstrate that hantaviruses regulate only β3 integrin directed endothelial cell functions and have no effect on β1 integrin functions. Since β3 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 β3 integrins may contribute to hantavirus pathogenesis.

Received January 23, 2002; accepted May 20, 2002