Pathogenic hantaviruses bind PSI domains present at the apex of inactive, bent, alphavbeta3 integrin conformers.

摘要

Hantaviruses cause two diseases, hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS), that are characterized by increased vascular permeability, hemorrhage and thrombocytopenia. Previous work demonstrated that pathogenic hantaviruses use beta3 integrins for cell entry. beta3 integrins regulate both vascular permeability and platelet function and have a functional role in hemorrhagic diseases that have a striking similarity to symptoms in hantavirus infected patients.; To determine the beta3 integrin domain used by pathogenic hantaviruses, domain swaps between recombinant human and murine beta3 were analyzed for their ability to confer hantavirus infection to non-susceptible cells. Analysis of the N-terminal PSI domain of human beta3 revealed that the first 39 residues were required for binding to pathogenic hantaviruses (NY-1V and HTNV). Purified polypeptides containing residues 1-53 or 1-136 inhibited hantavirus infection and binding. Mutation of Asp-39 abolished peptide inhibition and conversion of murine Asn-39 to human Asp-39 conferred infectivity to NY-1V and HTNV. These findings demonstrate hantavirus binding to specific residues within the beta3 integrin PSI domain.; Recent beta3 integrin structural studies revealed that alphavbeta3 exists in two different conformations: a bent, inactive conformation and an extended, active conformation. Extended conformations expose ligand binding head domains while bent conformations expose a unique beta3 integrin PSI domain at its apex. beta3 residues that confer cell susceptibility to pathogenic hantaviruses are within the PSI domain at the apex of bent integrin conformers. Further, recombinant beta3 integrins locked into bent or extended conformations revealed that pathogenic hantaviruses were able to use bent, but not extended, integrin conformers for infection.; These findings indicate that pathogenic hantaviruses interact with PSI domains of beta3 integrins present at the apex of inactive, bent alphavbeta3 conformations.; These findings suggest that pathogenic hantaviruses may dysregulate beta3 integrin function by directing alphavbeta3 into conformations which are incapable of binding to ECM ligands. Pathogenic hantaviruses may also direct immune responses to alphavbeta3 integrins which can further contribute to hemorrhagic disease or edema observed in HFRS and HPS patients. These findings provide insight into the role of beta3 integrins in hantavirus pathogenesis and provide a specific target for developing hantavirus therapeutics.