Andes virus recognition of human and Syrian hamster beta3 integrins is determined by an L33P substitution in the PSI domain.
Andes virus (ANDV) causes a fatal hantavirus pulmonary syndrome (HPS) in humans and Syrian hamsters. Human alpha(v)beta(3) integrins are receptors for several pathogenic hantaviruses, and the function of alpha(v)beta(3) integrins on endothelial cells suggests a role for alpha(v)beta(3) in hantavirus directed vascular permeability. We determined here that ANDV infection of human endothelial cells or Syrian hamster-derived BHK-21 cells was selectively inhibited by the high-affinity alpha(v)beta(3) integrin ligand vitronectin and by antibodies to alpha(v)beta(3) integrins. Further, antibodies to the beta(3) integrin PSI domain, as well as PSI domain polypeptides derived from human and Syrian hamster beta(3) subunits, but not murine or bovine beta(3), inhibited ANDV infection of both BHK-21 and human endothelial cells. These findings suggest that ANDV interacts with beta(3) subunits through PSI domain residues conserved in both Syrian hamster and human beta(3) integrins. Sequencing the Syrian hamster beta(3) integrin PSI domain revealed eight differences between Syrian hamster and human beta(3) integrins. Analysis of residues within the PSI domains of human, Syrian hamster, murine, and bovine beta(3) integrins identified unique proline substitutions at residues 32 and 33 of murine and bovine PSI domains that could determine ANDV recognition. Mutagenizing the human beta(3) PSI domain to contain the L33P substitution present in bovine beta(3) 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 beta(3) permitted PSI mutants to inhibit ANDV infection. Similarly, CHO cells transfected with the full-length bovine beta(3) integrin containing the P33L mutation permitted infection by ANDV. These findings indicate that human and Syrian hamster alpha(v)beta(3) integrins are key receptors for ANDV and that specific residues within the beta(3) integrin PSI domain are required for ANDV infection. Since L33P is a naturally occurring human beta(3) polymorphism, these findings further suggest the importance of specific beta(3) integrin residues in hantavirus infection. These findings rationalize determining the role of beta(3) integrins in hantavirus pathogenesis in the Syrian hamster model.
Matthys
Valery S
VS
Department of Molecular Genetics and Microbiology Stony Brook University, Stony Brook, NY 11794-5222, USA.
Gorbunova
Elena E
EE
Gavrilovskaya
Irina N
IN
Mackow
Erich R
ER
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D042783:Endothelial Cells / Q000821:virology; D006476:Orthohantavirus / Q000472:pathogenicity*; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism*; D008647:Mesocricetus; D051379:Mice; D011110:Polymorphism, Genetic; D011991:Receptors, Virus / Q000235:genetics*; D013045:Species Specificity
D039661:Integrin beta3; D011991:Receptors, Virus