Andes virus recognition of human beta3 integrin is determined by residue 33 within the beta3 integri...

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" Andes virus recognition of human beta3 integrin is determined by residue 33 within the beta3 integrin PSI domain "
Valery Sofie Matthys E. R. Mackow

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	52731
Doc. No	:	TL22685
Call number	:	‭3401718‬
Main Entry	:	Valery Sofie Matthys
Title & Author	:	Andes virus recognition of human beta3 integrin is determined by residue 33 within the beta3 integrin PSI domain\ Valery Sofie Matthys
College	:	State University of New York at Stony Brook
Date	:	2009
Degree	:	Ph.D.
student score	:	2009
Page No	:	120
Abstract	:	Andes virus (ANDV) causes a fatal hantavirus pulmonary syndrome (HPS) in humans and Syrian hamsters. Human avβ3 integrins are receptors for several pathogenic hantaviruses, and the function of avβ3 integrins on endothelial cells suggests a role for avβ3 in hantavirus directed vascular permeability. Here we determined that ANDV infection of human endothelial cells or Syrian hamster derived BHK-21 cells was selectively inhibited by vitronectin, a high affinity avβ3 integrin ligand, and by antibodies to avβ3 integrins. Further, antibodies to the β3 integrin PSI domain as well as PSI domain polypeptides derived from human and Syrian hamster β3 subunits, but not murine or bovine β3, inhibited ANDV infection of both BHK-21 and human endothelial cells. These findings suggest that ANDV interacts with β3 subunits through PSI domain residues conserved in both Syrian hamster and human β3 integrins. Sequencing the Syrian hamster β3 integrin PSI domain revealed 8 differences between Syrian hamster and human β3 integrins. Analysis of residues within the PSI domains of human, Syrian hamster, murine and bovine β3 integrins identified unique proline substitutions at residues 32-33 of murine and bovine PSI domains that could determine ANDV recognition. Mutagenizing the human β3 PSI domain to contain the L33P substitution present in bovine β3 integrin abolished the ability of the PSI domain to inhibit ANDV infectivity. Conversely, mutagenizing either the bovine PSI domain, P33L, or the murine PSI domain, S32P, to the residue present human β3 permitted PSI mutants to inhibit ANDV infection. Similarly, CHO cells transfected with the full length bovine β3 integrin containing the P33L mutation, permitted infection by ANDV. These findings indicate that human and Syrian hamster avβ3 integrins are key receptors for ANDV and that specific residues within the β3 integrin PSI domain are required for ANDV infection. Since L33P is a naturally occuring human β3 polymorphism these findings further suggest the importance of specific β3 integrin residues in hantavirus infection. These findings also rationalize determining the role of β3 integrins in hantavirus pathogenesis in the Syrian hamster model.
Subject	:	Biological sciences; Andes virus; Integrins; Plexin-Semaphorin-Integrin domain; Viral recognition; Virology; 0720:Virology
Added Entry	:	E. R. Mackow
Added Entry	:	State University of New York at Stony Brook