Integrin α _v β ₆ Is an RGD-Dependent Receptor for Coxsackievirus A9

Abstract

Coxsackievirus A9 (CAV9), a member of the Enterovirus genus of Picornaviridae, is a common human pathogen and is one of a significant number of viruses containing a functional arginine-glycine-aspartic acid (RGD) motif in one of their capsid proteins. Previous studies identified the RGD-recognizing integrin ␣ v ␤ 3 as its cellular receptor. However, integrin ␣ v ␤ 6 has been shown to be an efficient receptor for another RGDcontaining picornavirus, foot-and-mouth disease virus (FMDV). In view of the similarity in sequence context of the RGD motifs in CAV9 and FMDV, we investigated whether ␣ v ␤ 6 can also serve as a receptor for CAV9. We found that CAV9 can bind to purified ␣ v ␤ 6 and also to SW480 cells transfected with ␤ 6 cDNA, allowing expression of ␣ v ␤ 6 on their surface, but it cannot bind to mock-transfected cells. In addition, a higher yield of CAV9 was obtained in ␤ 6 -expressing cells than in mock-transfected cells. There was no similar enhancement in infection with an RGD-less CAV9 mutant. We also found ␤ 6 on the surface of GMK cells, a cell line which CAV9 infects efficiently by an RGD-dependent mechanism. Significantly, this infection is blocked by an antibody to ␣ v ␤ 6 , while this antibody did not block the low level of infection by the RGD-less mutant. Thus, integrin ␣ v ␤ 6 is an RGD-dependent receptor for CAV9 and may be important in natural CAV9 infections.Coxsackievirus A9 (CAV9), a member of the Enterovirus genus of the Picornaviridae family, is a common human pathogen that causes central nervous system infections and myocarditis as well as a range of milder illnesses (11, 43). The picornavirus particle is about 28 nm in diameter and consists of a naked capsid with icosahedral symmetry, surrounding a positive sense RNA genome of around 7,100 to 8,500 nucleotides (41). The capsid is made up of 60 copies of each of four proteins, VP1 to VP4, and interacts with receptors during the early stages of infection. A number of picornavirus receptors have been identified, and they include several integrins (9). Integrins are named for their role in integrating the intracellular cytoskeleton with the extracellular matrix and participate in a number of cell-cell, cell-matrix interactions. They are heterodimeric proteins with one ␣ and one ␤ subunit, and each contains an exodomain, the site of interaction with ligands, a transmembrane region, and a cytoplasmic domain. The 8 known ␤ subunits and 14 known ␣ subunits combine to give at least 21 different heterodimeric combinations (16,38,40).The arginine-glycine-aspartic acid (RGD) motif was the first integrin-binding sequence to be identified (38) and is recognized by several integrins (␣

Integrin αvβ1 promotes infection by human metapneumovirus

“…Furthermore, RGD peptides inhibited hMPV at sub-micromolar concentrations, whereas RGE peptides had a minimal effect that was not statistically significant. The degree of inhibition was modest, but it is noteworthy that similar levels of inhibition for other viruses often require millimolar concentrations of peptide (27,(33)(34)(35)(36).…”

“…2 B and C), suggesting a specific effect of the GRGDSP peptide on infection by hMPV. Although the inhibitory effect of the linear GRGDSP peptide is modest, the magnitude of the infectivity blockade approximates that achieved in studies of other viruses known to engage integrins (27,(33)(34)(35)(36).…”

“…In many cases, integrin-ligand interactions are dependent on divalent cations, including Ca 2ϩ and Mg 2ϩ (19). Attachment of integrinusing viruses to RGD-binding integrins is diminished by the divalent cation chelator EDTA (19,24,(31)(32)(33). We tested the effect of EDTA on hMPV binding and infection of cells using a quantitative immunostaining assay.…”

Influenza Promotes Collagen Deposition via αvβ6 Integrin-mediated Transforming Growth Factor β Activation

“…Our data demonstrate that inhibiting the function of ␣v␤6 integrin does not alter the cellular uptake of influenza virus in epithelial cells. Furthermore, in contrast with the picornavirus coat proteins (39), neither of the influenza coat proteins NA or HA contain an RGD sequence, which is required for interaction with TGF␤-activating integrins. Interestingly, both influenza polymerase basic proteins 1 and 2 (PB1-2) contain an RGD sequence, which is conserved across all influenza strains.…”

“…The ␣v␤6 integrin acts as a receptor for epithelial cell entry of the picornavirus Foot-and-Mouth disease in cattle (37,38), coxsackievirus A9 in humans (39), and human parechovirus (40). Similarly, fusion of the herpesvirus Epstein-Barr with epithelial cells has been shown to involve ␣v␤6 as well as ␣v␤5, and ␣v␤8 integrins (41)(42)(43).…”