EFFICIENT INFECTION OF CELLS IN CULTURE BY TYPE-O FOOT-AND-MOUTH-DISEASE-VIRUS REQUIRES BINDING TO CELL-SURFACE HEPARAN-SULFATE

Foot-and-mouth disease virus (FMDV) enters cells by attaching to cellu lar receptor molecules of the integrin family, one of which has been i dentified as the RGD-binding integrin alpha v beta 3. Were we report t hat, in addition to an integrin binding site, type O strains of FMDV s hare with natural ligands of alpha v beta 3 (i.e,, vitronectin and fib ronectin) a specific affinity for heparin and that binding to the cell ular form of this sulfated glycan, heparan sulfate, is required for ef ficient infection of cells in culture. Binding of the virus to parafor maldehyde-fixed cells mas powerfully inhibited by agents such as hepar in, that compete with heparan sulfate or by agents that compete for he paran sulfate (platelet factor 4) or that inactivate it (heparinase), Neither chondroitin sulfate, a structurally related component of the e xtracellular matrix, nor dextran sulfate appreciably inhibited binding , The functional importance of heparan sulfate binding was demonstrate d by the facts that (i) infection of live cells by FMDV could also be blocked specifically by heparin, albeit at a much higher concentration of inhibitor; (ii) pretreatment of cells with heparinase reduced the number of plaques formed compared with that for untreated tells; and ( iii) mutant cell lines deficient in heparan sulfate expression were un able to support plaque formation by FMDV, even though they remained eq ually susceptible to another picornavirus, bovine enterovirus. The res ults show that entry of type O FMDV into cells is a complex process an d suggest that the initial contact with the cell surface is made throu gh heparan sulfate.