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Cellular receptors for species B adenoviruses
Umeå University, Faculty of Medicine, Clinical Microbiology.
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 [en]
Adenovirus, CD46, CD80, CD86, Species B, Receptor, Internalization, Infection, Tropism
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-1351ISBN: 978-91-7264-409-0 (print)OAI: oai:DiVA.org:umu-1351DiVA: diva2:140735
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
List of papers
1. Adenovirus type 11 uses CD46 as a cellular receptor
Open this publication in new window or tab >>Adenovirus type 11 uses CD46 as a cellular receptor
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2003 (English)In: Journal of Virology, ISSN 0022-538X, Vol. 77, no 17, 9183-9191 p.Article in journal (Refereed) Published
Abstract [en]

The 51 human adenovirus serotypes are divided into six species (A to F). Many adenoviruses use the coxsackie-adenovirus receptor (CAR) for attachment to host cells in vitro. Species B adenoviruses do not compete with CAR-binding serotypes for binding to host cells, and it has been suggested that species B adenoviruses use a receptor other than CAR. Species B adenoviruses mainly cause disease in the respiratory tract, the eyes, and in the urinary tract. Here we demonstrate that adenovirus type 11 (Ad11; of species B) binds to Chinese hamster ovary (CHO) cells transfected with CD46 (membrane cofactor protein)-cDNA at least 10 times more strongly than to CHO cells transfected with cDNAs encoding CAR or CD55 (decay accelerating factor). Nonpermissive CHO cells were rendered permissive to Ad11 infection upon transfection with CD46-cDNA. Soluble Ad11 fiber knob but not Ad7 or Ad5 knob inhibited binding of Ad11 virions to CD46-transfected cells, and anti-CD46 antibodies inhibited both binding of and infection by Ad11. From these results we conclude that CD46 is a cellular receptor for Ad11.

Identifiers
urn:nbn:se:umu:diva-2548 (URN)10.1128/JVI.77.17.9183-9191.2003 (DOI)12915534 (PubMedID)
Available from: 2007-09-17 Created: 2007-09-17 Last updated: 2010-01-27Bibliographically approved
2. CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7
Open this publication in new window or tab >>CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7
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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
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-20667 (URN)10.1128/JVI.79.22.14429-14436.2005 (DOI)16254377 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2012-08-08Bibliographically approved
3. CD46 but not CD80 or CD86 serves as a cellular receptor for selected species B adenoviruses on human epithelial cells
Open this publication in new window or tab >>CD46 but not CD80 or CD86 serves as a cellular receptor for selected species B adenoviruses on human epithelial cells
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(English)Manuscript (Other academic)
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-2550 (URN)
Available from: 2007-09-17 Created: 2007-09-17 Last updated: 2012-08-08
4. Adenovirus type 11 binding alters the conformation of its receptor CD46.
Open this publication in new window or tab >>Adenovirus type 11 binding alters the conformation of its receptor CD46.
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2007 (English)In: Nature Structural & Molecular Biology, ISSN 1545-9993, E-ISSN 1545-9985, Vol. 14, no 2, 164-166 p.Article in journal (Refereed) Published
Abstract [en]

Adenoviruses (Ads) are important human pathogens and valuable gene delivery vehicles. We report here the crystal structure of the species B Ad11 knob complexed with the Ad11-binding region of its receptor CD46. The conformation of bound CD46 differs profoundly from its unbound state, with the bent surface structure straightened into an elongated rod. This mechanism of interaction is likely to be conserved among many pathogens that target CD46 or related molecules.

Identifiers
urn:nbn:se:umu:diva-20700 (URN)10.1038/nsmb1190 (DOI)17220899 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2011-06-09

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