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CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
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2005 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 79, no 22, 14429-14436 p.Article in journal (Refereed) Published
Abstract [en]

The 51 human adenovirus serotypes are divided into six species (A to F). Adenovirus serotypes from all species except species B utilize the coxsackie-adenovirus receptor for attachment to host cells in vitro. Species B adenoviruses primarily cause ocular and respiratory tract infections, but certain serotypes are also associated with renal disease. We have previously demonstrated that adenovirus type 11 (species B) uses CD46 (membrane cofactor protein) as a cellular receptor instead of the coxsackie-adenovirus receptor (A. Segerman et al., J. Virol. 77:9183-9191, 2003). In the present study, we found that transfection with human CD46 cDNA rendered poorly permissive Chinese hamster ovary cells more permissive to infection by all species B adenovirus serotypes except adenovirus types 3 and 7. Moreover, rabbit antiserum against human CD46 blocked or efficiently inhibited all species B serotypes except adenovirus types 3 and 7 from infecting human A549 cells. We also sequenced the gene encoding the fiber protein of adenovirus type 50 (species B) and compared it with the corresponding amino acid sequences from selected serotypes, including all other serotypes of species B. From the results obtained, we conclude that CD46 is a major cellular receptor on A549 cells for all species B adenoviruses except types 3 and 7.

Place, publisher, year, edition, pages
American Society for Microbiology , 2005. Vol. 79, no 22, 14429-14436 p.
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-20667DOI: 10.1128/JVI.79.22.14429-14436.2005PubMedID: 16254377OAI: oai:DiVA.org:umu-20667DiVA: diva2:209272
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2012-08-08Bibliographically approved
In thesis
1. Cellular receptors for species B adenoviruses
Open this publication in new window or tab >>Cellular receptors for species B adenoviruses
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenoviruses belong to the most common human pathogens. The severity of infection varies greatly, from subclinical to lethal, depending on the virus type and immune status of the infected host. The 51 known human adenovirus serotypes are divided into six species (A-F) based on characteristics such as tropism. Species B adenoviruses, which are the subjects of this thesis, are further divided into subspecies B:1 that contains Ad3, Ad7, Ad16, Ad21 and Ad50 and subspecies B:2 that contains Ad11, Ad14, Ad34 and Ad35. Species B adenoviruses primarily cause ocular and respiratory tract infections, but certain serotypes (Ad11, Ad34 and Ad35) are also associated with renal disease.

The main aim of this thesis was to identify and characterize cellular receptors for species B adenoviruses. This will ultimately help to understand the diverse tropism shown by different adenoviruses and perhaps contribute to development of antivirals. Also, since adenoviruses are among the most commonly used vector for gene therapy it is of importance to characterize the initial steps of adenovirus life cycle.

Members of species B adenoviruses have been shown to utilize both the complement regulating membrane cofactor protein (MCP), i.e. CD46, and a still unknown receptor. CD80 and CD86, usually found on antigen-presenting cells, have also been suggested as receptors

We found first that Ad11 used CD46 as a cellular receptor on respiratory A549 cells, and subsequently that CD46 is a cellular receptor for all species B adenovirus serotypes, except for adenovirus types 3 and 7, using cells that represent the tropism of species B adenoviruses, i.e. respiratory, conjunctival and renal epithelial cells.

We further compared the relative roles of CD46 with CD80 and CD86 using cells that represent species B adenovirus tropism. Using soluble candidate receptors and antibodies against corresponding receptors to challenge virus binding to and infection of cells, we found that on these cells, CD46 is a cellular receptor for all species B adenoviruses except Ad3 and Ad7, and that CD80 and CD86 do not play an important role.

We have further pinpointed the interaction site for Ad11 on CD46 by X-ray crystallography. The extracellular region of CD46 contains four short consensus repeats (SCR1-4) of which the outermost N-terminal SCR1 and SCR2 mediate binding to Ad11. This interaction was confirmed by inhibiting infection and binding of Ad11 to A549 cells using soluble SCR1-2 fragments. Surprisingly the conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. Viral proteins can sometimes undergo large conformational changes upon receptor binding, but this is, to the best of our knowledge, the first example of a virus protein dramatically changing the overall structure of its receptor. CD46 serves as a receptor for a large number of viral and bacterial pathogens and it is structurally and functionally related to other viral receptors such as CD21 and CD55. The mode of interaction presented here may serve as a conceptual framework for studies of many other receptors that are constructed from SCR domains.

Place, publisher, year, edition, pages
Umeå: Klinisk mikrobiologi, 2007. 72 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1123
Keyword
Adenovirus, CD46, CD80, CD86, Species B, Receptor, Internalization, Infection, Tropism
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-1351 (URN)978-91-7264-409-0 (ISBN)
Public defence
2007-10-05, Betula, 6M, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2007-09-17 Created: 2007-09-17 Last updated: 2010-01-18Bibliographically approved
2. Adenovirus species B interactions with CD46
Open this publication in new window or tab >>Adenovirus species B interactions with CD46
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenoviruses (Ad) are double-stranded (ds) DNA, non-enveloped viruses. There are seven species (A-G) of human Ads with 52 knownserotypes to date. Human Ads cause a broad range of pathologies, ranging from upper respiratory tract infections to persistent urinary tract infections. The main determinant for Ads tropism in vitro is the protruding, antenna-like, fiber protein. The fiberknob is responsible for the main interaction with the attachment receptor of the host cell. Most Ad species use the coxsackie- adenovirus receptor (CAR) as their main attachment receptor. Most species B Ads, however use CD46. CD46 is a cell surface complement regulatory protein, which is expressed on all nucleated cells in humans. Species B Ads exhibit a low seroprevalenc in the human population, making these Ads promising vector candidates for gene therapy. We have studied human Ad species B members, serotypes 7 and 11 (Ad7 and Ad11), as well as their interaction with CD46. Our first experiments showed that all species B Ads use CD46 as their main attachment receptor, with the exception of Ad3 and Ad7. Second, we performed mutational studies of recombinant Ad11p fiberknobs. These studies showed that arginine 279 in the Ad 11 fiberknob is necessary for CD46 binding. Finally we studied the effect of Ad11 binding to CD46. The results indicate that CD46 is rapidly downregulated on the cell surface after Ad11 binding. These results may provide a further understanding of the basic biology and pathology of species B Ads and may also be useful in construction of gene therapy vectors based on species B Ads.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1480
Keyword
Adenovirus 11, CD46
National Category
Microbiology
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-52075 (URN)978-91-7459-368-6 (ISBN)
Public defence
2012-03-02, Sal E04, Biomedicinhuset, Byggnad 6E, Norrlands universitetssjukhus, Umeå, 20:42 (English)
Opponent
Supervisors
Available from: 2012-02-10 Created: 2012-02-08 Last updated: 2012-02-10Bibliographically approved

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Marttila, MarkoGustafsson, DanWadell, GöranArnberg, Niklas

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