Mammalian adenoviruses (AdVs) comprise more than ~350 types including over 100 human (HAdVs) and just three mouse AdVs (MAdVs). While most HAdVs initiate
infection by high affinity/avidity binding of their fiber knob (FK)
protein to either coxsackievirus AdV receptor (CAR), CD46 or
desmoglein (DSG)-2, MAdV-1 (M1)
infection requires
arginine-
glycine-
aspartate (RGD) binding
integrins. To identify the receptors mediating MAdV
infection we generated five novel reporter viruses for MAdV-1/-2/-3 (M1, M2, M3) transducing permissive murine (m) CMT-93 cells, but not B16 mouse
melanoma cells expressing mCAR, human (h) CD46 or hDSG-2. Recombinant M1 or M3 FKs cross-blocked M1 and M3 but not M2
infections. Profiling of murine and human cells expressing RGD-binding
integrins suggested that αvβ6 and αvβ8 heterodimers are associated with M1 and M3
infections. Ectopic expression of mβ6 in B16 cells strongly enhanced M1 and M3 binding,
infection, and progeny production comparable with mαvβ6-positive CMT-93 cells, whereas mβ8 expressing cells were more permissive to M1 than M3. Anti-
integrin antibodies potently blocked M1 and M3 binding and
infection of CMT-93 cells and hαvβ8-positive M000216 cells. Soluble
integrin αvβ6, and synthetic
peptides containing the RGDLXXL sequence derived from FK-M1, FK-M3 and foot and mouth disease virus coat
protein strongly interfered with M1/M3
infections, in agreement with high affinity interactions of FK-M1/FK-M3 with αvβ6/αvβ8, determined by surface plasmon resonance measurements. Molecular docking simulations of ternary complexes revealed a bent conformation of RGDLXXL-containing FK-M3
peptides on the subunit interface of αvβ6/β8, where the distal
leucine residue
dips into a hydrophobic pocket of β6/8, the
arginine residue ionically engages αv aspartate215, and the
aspartate residue coordinates a divalent
cation in αvβ6/β8. Together, the RGDLXXL-bearing FKs are part of an essential mechanism for M1/M3
infection engaging murine and human αvβ6/8
integrins. These
integrins are highly conserved in other mammals, and may favour cross-species virus transmission.