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Mechanisms involved in adenovirus binding to and infection of host cells
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. (Niklas Arnberg)
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 [en]
Adenovirus, binding, infection, lactoferrin, coagulation factor IX and X, fiber
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-27646ISBN: 978-91-7264-876-0 (print)OAI: oai:DiVA.org:umu-27646DiVA: diva2:276874
Public defence
2009-12-04, Betula, Byggnad 6M, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2009-11-16 Created: 2009-11-12 Last updated: 2011-04-07Bibliographically approved
List of papers
1. Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and infection of epithelial cells
Open this publication in new window or tab >>Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and infection of epithelial cells
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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
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-20697 (URN)10.1128/JVI.01995-06 (DOI)17079302 (PubMedID)
Available from: 2009-03-24 Created: 2009-03-24 Last updated: 2017-12-13Bibliographically approved
2. LactoferricinH promotes transduction of adenovirus type 5 in respiratory epithelial cells
Open this publication in new window or tab >>LactoferricinH promotes transduction of adenovirus type 5 in respiratory epithelial cells
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-27697 (URN)
Available from: 2009-11-16 Created: 2009-11-16 Last updated: 2009-11-16Bibliographically approved
3. Coagulation factors IX and X enhance binding and infection of adenovirus types 5 and 31 in human epithelial cells
Open this publication in new window or tab >>Coagulation factors IX and X enhance binding and infection of adenovirus types 5 and 31 in human epithelial cells
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2009 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, no 8, 3816-3825 p.Article in journal (Refereed) Published
Abstract [en]

Most adenoviruses bind directly to the coxsackie and adenovirus receptor (CAR) on target cells in vitro, but recent research has shown that adenoviruses can also use soluble components in body fluids for indirect binding to target cells. These mechanisms have been identified upon addressing the questions of how to de- and retarget adenovirus-based vectors for human gene and cancer therapy, but the newly identified mechanisms also suggest that the role of body fluids and their components may also be of importance for natural, primary infections. Here we demonstrate that plasma, saliva, and tear fluid promote binding and infection of adenovirus type 5 (Ad5) in respiratory and ocular epithelial cells, which corresponds to the natural tropism of most adenoviruses, and that plasma promotes infection by Ad31. By using a set of binding and infection experiments, we also found that Ad5 and Ad31 require coagulation factors IX (FIX) or X (FX) or just FIX, respectively, for efficient binding and infection. The concentrations of these factors that were required for maximum binding were 1/100th of the physiological concentrations. Preincubation of virions with heparin or pretreatment of cells with heparinase I indicated that the role of cell surface heparan sulfate during FIX- and FX-mediated adenovirus binding and infection is mechanistically serotype specific. We conclude that the use of coagulation factors by adenoviruses may be of importance not only for the liver tropism seen when administering adenovirus vectors to the circulation but also during primary infections by wild-type viruses of their natural target cell types.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-21099 (URN)10.1128/JVI.02562-08 (DOI)19158249 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2017-12-13Bibliographically approved
4. Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence
Open this publication in new window or tab >>Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence
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2009 (English)In: PloS one, ISSN 1932-6203, Vol. 4, no 12, e8484- p.Article in journal (Refereed) Published
Abstract [en]

The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.

Identifiers
urn:nbn:se:umu:diva-42372 (URN)10.1371/journal.pone.0008484 (DOI)20041185 (PubMedID)
Available from: 2011-04-07 Created: 2011-04-07 Last updated: 2011-04-07Bibliographically approved

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