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Adenovirus 11p downregulates CD46 early in infection
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.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
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2010 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, 474-482 p.Article in journal (Refereed) Published
Abstract [en]

Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.

Place, publisher, year, edition, pages
2010. Vol. 405, no 2, 474-482 p.
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-35716DOI: 10.1016/j.virol.2010.06.026ISI: 000281130500023PubMedID: 20638094OAI: oai:DiVA.org:umu-35716DiVA: diva2:346473
Available from: 2010-09-01 Created: 2010-09-01 Last updated: 2012-02-24Bibliographically approved
In thesis
1. Human adenoviruses: new bioassays for antiviral screening and CD46 interaction
Open this publication in new window or tab >>Human adenoviruses: new bioassays for antiviral screening and CD46 interaction
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adenoviruses are common pathogens all over the world. The majority of the population has at some point been infected with an adenovirus. Although severe disease can occur in otherwise healthy individuals an adenovirus infection is most commonly self limited in these cases. For immunocompromised individuals however, adenoviruses can be life-threatening pathogens capable of causing disseminated disease and multiple organ failure. Still there is no approved drug specific for treatment of adenovirus infections. We have addressed this using a unique whole cell viral replication reporter gene assay to screen small organic molecules for anti-adenoviral effect. This RCAd11pGFP-vector based assay allowed screening without any preconceived idea of the mechanism for adenovirus inhibition. As a result of the screening campaign 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid turned out to be a potent inhibitor of adenoviral replication. To establish a structure-activity relationship a number of analogs were synthesized and evaluated for their anti-adenoviral effect. The carboxylic acid moiety of the molecule was important for efficient inhibition of adenovirus replication.

There are 54 adenovirus types characterized today and these are divided into seven species, A-G. The receptors used by species B and other adenoviruses are not fully characterized. CD46 is a complement regulatory molecule suggested to be used by all species B types and some species D types but this is not established. We have designed a new bioassay for assessment of the interaction between adenoviruses and CD46 and investigated the CD46-binding capacity of adenovirus types indicated to interact with CD46. We concluded that Ad11p, Ad34, Ad35, and Ad50 clearly bind CD46 specifically, whereas Ad3p, Ad7p, Ad14, and Ad37 do not.

CD46 is expressed on all human nucleated cells and serves as a receptor for a number of different bacteria and viruses. Downregulation of CD46 on the cell surface occurs upon binding by some of these pathogens. We show that early in infection Ad11p virions downregulate CD46 upon binding to a much higher extent than the complement regulatory molecules CD55 and CD59.

These findings may lead to a better understanding of the pathogenesis of adenoviruses in general and species B adenoviruses in particular and hopefully we have discovered a molecule that can be the basis for development of new anti-adenoviral drugs.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2010. 81 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1366
Keyword
Adenovirus, CD46, hemagglutination, antiviral, small molecule, screening
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-35733 (URN)978-91-7459-056-2 (ISBN)
Public defence
2010-09-24, Sal 914, 9tr NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-09-03 Created: 2010-09-01 Last updated: 2014-04-25Bibliographically 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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Gustafsson, Dan JAndersson, Emma KMarttila, MarkoLindman, KristinaStrand, MårtenMei, Ya-Fang

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