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Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection


Trinh, H V; Lesage, G; Chennamparampil, V; Vollenweider, B; Burckhardt, C J; Schauer, S; Havenga, M; Greber, U F; Hemmi, S (2012). Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection. Journal of Virology, 86(3):1623-1637.

Abstract

The species B human adenoviruses (short Ad) infect cells upon attaching to CD46 or desmoglein-2 (DSG-2) by one or several of their twelve fiber knob trimers (FK). To test whether DSG-2 and CD46 simultaneously serve as virus receptors for 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 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 receptor, we performed gain-of-function studies in rodent cells. 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 plasmon resonance studies. Ad3/7 FK binding to immobilized CD46 at low density was not detected, unlike Ad11/35-FK. At higher CD46 densities, however, Ad3/7-FK bound to CD46 with only 15-fold higher dissociation constants than Ad11/35-FK. These data show that an avidity mechanism for Ad3/7 binding to CD46 leads to infection of CD46-positive cells.

The species B human adenoviruses (short Ad) infect cells upon attaching to CD46 or desmoglein-2 (DSG-2) by one or several of their twelve fiber knob trimers (FK). To test whether DSG-2 and CD46 simultaneously serve as virus receptors for 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 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 receptor, we performed gain-of-function studies in rodent cells. 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 plasmon resonance studies. Ad3/7 FK binding to immobilized CD46 at low density was not detected, unlike Ad11/35-FK. At higher CD46 densities, however, Ad3/7-FK bound to CD46 with only 15-fold higher dissociation constants than Ad11/35-FK. These data show that an avidity mechanism for Ad3/7 binding to CD46 leads to infection of CD46-positive cells.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2012
Deposited On:06 Jan 2012 16:21
Last Modified:05 Apr 2016 15:14
Publisher:American Society for Microbiology
ISSN:0022-538X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1128/JVI.06181-11
PubMed ID:22130529
Permanent URL: http://doi.org/10.5167/uzh-53021

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