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Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and infection of epithelial cells
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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2007 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 81, no 2, 954-963 p.Article in journal (Refereed) Published
Abstract [en]

Most adenoviruses bind to the coxsackie- and adenovirus receptor (CAR). Surprisingly, CAR is not expressed apically on polarized cells and is thus not easily available to viruses. Consequently, alternative mechanisms for entry of coxsackievirus and adenovirus into cells have been suggested. We have found that tear fluid promotes adenovirus infection, and we have identified human lactoferrin (HLf) as the tear fluid component responsible for this effect. HLf alone was found to promote binding of adenovirus to epithelial cells in a dose-dependent manner and also infection of epithelial cells by adenovirus. HLf was also found to promote gene delivery from an adenovirus-based vector. The mechanism takes place at the binding stage and functions independently of CAR. Thus, we have identified a novel binding mechanism whereby adenovirus hijacks HLf, a component of the innate immune system, and uses it as a bridge for attachment to host cells.

Place, publisher, year, edition, pages
American Society for Microbiology , 2007. Vol. 81, no 2, 954-963 p.
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-20697DOI: 10.1128/JVI.01995-06PubMedID: 17079302OAI: oai:DiVA.org:umu-20697DiVA: diva2:209357
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Mechanisms involved in adenovirus binding to and infection of host cells
Open this publication in new window or tab >>Mechanisms involved in adenovirus binding to and infection of host cells
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The adenovirus (Ad) family consists of 52 different human types, which are divided into seven species (A-G). Human Ads cause disease in the respiratory tract, lymphoid tissue, intestine, urinary tract, and/or in the eye. Most, but not all Ads have been demonstrated to use the coxsackie-adenovirus receptor (CAR) as an efficient receptor in vitro, but CAR has been questioned as an in vivo-receptor for various reasons. Thus, there are reasons to believe that Ads use other mechanisms for binding to target cells. In an attempt to investigate the impact of tear fluid during in vitro infection of ocular Ads (i.e. Ad37), using corneal cells, we found that human tear fluid promoted infection of an Ad with pronounced respiratory tropism (i.e. Ad5) used here as a control, but surprisingly not of Ad37. Furthermore using a virus overlay protein blotting assay we found that Ad5 bound to several tear fluid proteins. One of these, human lactoferrin (hLf) which is a component that belongs to the innate immune system in various body fluids, was alone able to promote both binding and infection of all species C Ads (Ad1, Ad2, Ad5, Ad6) in epithelial cells. hLf was also found to promote gene delivery (GFP) from an Ad5-based vector. Further we have identified lactoferricin (Lfcin), the N-terminal part of hLf, as to be responsible for this effect. We also show that plasma, saliva, and tear fluid promote infection of Ad5 in respiratory and ocular epithelial cells, and that plasma promotes infection of Ad31. The component in plasma that is responsible for this effect is likely to be coagulation factor IX (FIX) and X (FX), since both these factors were able to promote binding and infection of Ad5 and/or Ad31 in epithelial cells. Finally, we show that the excess of fiber production from initial Ad infection and the release of fibers before the particle itself is released caused masking of the tropism-specific receptors in both infected and non-infected surrounding cells. This means that the overproduction of fibers affects the ability of Ad to spread within tissues.

We conclude that soluble components in body fluids, such as hLf, FIX, and FX have the ability to mediate binding and infection of selected human Ads (species C and Ad31) in epithelial cells that represent the tropism of these Ads. We suggest that these components may serve as bridges between the virion and the cell surface. This is contributes to the knowledge about Ad lifecycle, and might help to improve the de-/retargeting of gene therapy based on Ad vectors.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 71 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1301
Keyword
Adenovirus, binding, infection, lactoferrin, coagulation factor IX and X, fiber
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-27646 (URN)978-91-7264-876-0 (ISBN)
Public defence
2009-12-04, Betula, Byggnad 6M, NUS, Umeå, 09:00 (English)
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Available from: 2009-11-16 Created: 2009-11-12 Last updated: 2011-04-07Bibliographically approved

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