title: Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection.
abstract: The species B human adenoviruses (HAdVs) infect cells upon attaching to CD46 or desmoglein 2 (DSG-2) by one or several of their 12 fiber knob trimers (FKs). To test whether DSG-2 and CD46 simultaneously serve as virus receptors for adenovirus type 3 (Ad3), we performed individual and combined CD46/DSG-2 loss-of-function studies in human lung A549 and 16HBE14o cells. Our results suggest that in these cells, DSG-2 functions as a major attachment receptor for Ad3, whereas CD46 exerts a minor contribution to virus attachment and uptake in the range of ∼10%. However, in other cells the role of CD46 may be more pronounced depending on, e.g., the expression levels of the receptors. To test if avidity allows Ad3/7 to use CD46 as a receptor, we performed gain-of-function studies. The cell surface levels of ectopically expressed CD46 in CHO or human M010119 melanoma cells lacking DSG-2 positively correlated with Ad3/7 infections, while Ad11/35 infections depended on CD46 but less on CD46 levels. Antibody-cross-linked soluble CD46 blocked Ad3/7/11/35 infections, while soluble CD46 alone blocked Ad11/35 but not Ad3/7. Soluble Ad3/7-FKs poorly inhibited Ad3/7 infection of CHO-CD46 cells, illustrating that Ad3/7-FKs bind with low affinity to CD46. This was confirmed by Biacore studies. Ad3/7-FK binding to immobilized CD46 at low density was not detected, unlike that of Ad11/35-FK. At higher CD46 densities, however, Ad3/7-FK bound to CD46 with only 15-fold-higher dissociation constants than those of Ad11/35-FK. These data show that an avidity mechanism for Ad3/7 binding to CD46 leads to infection of CD46-positive cells.
authors: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors: Hung V
authors: HV
authors: Trinh
authors: Guillaume
authors: G
authors: Lesage
authors: Venus
authors: V
authors: Chennamparampil
authors: Benedikt
authors: B
authors: Vollenweider
authors: Christoph J
authors: CJ
authors: Burckhardt
authors: Stefan
authors: S
authors: Schauer
authors: Menzo
authors: M
authors: Havenga
authors: Urs F
authors: UF
authors: Greber
authors: Silvio
authors: S
authors: Hemmi
mesh_terms: D000256:Adenoviridae / Q000276:immunology* / Q000502:physiology; D000257:Adenoviridae Infections; D000818:Animals; D000915:Antibody Affinity; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D051916:Membrane Cofactor Protein / Q000276:immunology*; D011991:Receptors, Virus / Q000502:physiology; D020349:Surface Plasmon Resonance
chemical_list: D051916:Membrane Cofactor Protein; D011991:Receptors, Virus