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BETA
Marttila, Marko
Publications (7 of 7) Show all publications
Aplander, K., Marttila, M., Manner, S., Arnberg, N., Sterner, O. & Ellervik, U. (2011). Molecular wipes: application to epidemic keratoconjuctivitis. Journal of Medicinal Chemistry, 54(19), 6670-6675
Open this publication in new window or tab >>Molecular wipes: application to epidemic keratoconjuctivitis
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2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 19, p. 6670-6675Article in journal (Refereed) Published
Abstract [en]

Epidemic keratoconjunctivitis (EKC) is a severe disease of the eye, caused by members of the Adenoviridae (Ad) family, with symptoms such as keratitis, conjunctivitis, pain, edema, and reduced vision that may last for months or years. There are no vaccines or antiviral drugs available to prevent or treat EKC. It was found previously that EKC-causing Ads use sialic acid as a cellular receptor and demonstrated that soluble, sialic acid-containing molecules can prevent infection. In this study, multivalent sialic acid constructs based on 10,12-pentacosadiynoic acid (PDA) have been synthesized, and these constructs are shown to be efficient inhibitors of Ad binding (IC(50) = 0.9 mu M) and Ad infectivity (IC(50) = 0.7 mu M). The mechanism of action is to aggregate virus particles and thereby prevent them from binding to ocular cells. Such formulations may be used for topical treatment of adenovirus-caused EKC.

Place, publisher, year, edition, pages
Easton, Pa.: American Chemical Society, 2011
Keywords
sialic acid, colorimetric detection, adenovirus type 37, cellular receptor, potent inhibitors, influenza-virus, keratoconjunctivitis, polymerization, infection, liposomes
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-49226 (URN)10.1021/jm200545m (DOI)000295546200022 ()
Available from: 2011-11-11 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
Gustafsson, D. J., Andersson, E. K., Hu, Y.-L., Marttila, M., Lindman, K., Strand, M., . . . Mei, Y.-F. (2010). Adenovirus 11p downregulates CD46 early in infection. Virology, 405(2), 474-482
Open this publication in new window or tab >>Adenovirus 11p downregulates CD46 early in infection
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2010 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 405, no 2, p. 474-482Article 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.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-35716 (URN)10.1016/j.virol.2010.06.026 (DOI)000281130500023 ()20638094 (PubMedID)
Available from: 2010-09-01 Created: 2010-09-01 Last updated: 2018-06-08Bibliographically approved
Persson, B. D., Müller, S., Reiter, D. M., Schmitt, B. B., Marttila, M., Sumowski, C. V., . . . Stehle, T. (2009). An arginine switch in the species B adenovirus knob determines high-affinity engagement of cellular receptor CD46.. Journal of Virology, 83(2), 673-686
Open this publication in new window or tab >>An arginine switch in the species B adenovirus knob determines high-affinity engagement of cellular receptor CD46.
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2009 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 83, no 2, p. 673-686Article in journal (Refereed) Published
Abstract [en]

Adenoviruses (Ads) are icosahedral, nonenveloped viruses with a double-stranded DNA genome. The 51 known Ad serotypes exhibit profound variations in cell tropism and disease types. The number of observed Ad infections is steadily increasing, sometimes leading to fatal outcomes even in healthy individuals. Species B Ads can cause kidney infections, hemorrhagic cystitis, and severe respiratory infections, and most of them use the membrane cofactor protein CD46 as a cellular receptor. The crystal structure of the human Ad type 11 (Ad11) knob complexed with CD46 is known; however, the determinants of CD46 binding in related species B Ads remain unclear. We report here a structural and functional analysis of the Ad11 knob, as well as the Ad7 and Ad14 knobs, which are closely related in sequence to the Ad11 knob but have altered CD46-binding properties. The comparison of the structures of the three knobs, which we determined at very high resolution, provides a platform for understanding these differences and allows us to propose a mechanism for productive high-affinity engagement of CD46. At the center of this mechanism is an Ad knob arginine that needs to switch its orientation in order to engage CD46 with high affinity. Quantum chemical calculations showed that the CD46-binding affinity of Ad11 is significantly higher than that of Ad7. Thus, while Ad7 and Ad14 also bind CD46, the affinity and kinetics of these interactions suggest that these Ads are unlikely to use CD46 productively. The proposed mechanism is likely to determine the receptor usage of all CD46-binding Ads.

National Category
Medical and Health Sciences
Research subject
Medical Virology
Identifiers
urn:nbn:se:umu:diva-21100 (URN)10.1128/JVI.01967-08 (DOI)18987134 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2018-06-09Bibliographically approved
Persson, B. D., Reiter, D. M., Marttila, M., Mei, Y.-F., Casasnovas, J. M., Arnberg, N. & Stehle, T. (2007). Adenovirus type 11 binding alters the conformation of its receptor CD46.. Nature Structural & Molecular Biology, 14(2), 164-166
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, p. 164-166Article 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: 2018-06-09
Johansson, C., Jonsson, M., Marttila, M., Persson, D., Fan, X.-L., Skog, J., . . . Arnberg, N. (2007). Adenoviruses use lactoferrin as a bridge for CAR-independent binding to and infection of epithelial cells. Journal of Virology, 81(2), 954-963
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, p. 954-963Article 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: 2018-06-09Bibliographically approved
Marttila, M., Persson, D., Gustafsson, D., Liszewski, M. K., Atkinson, J. P., Wadell, G. & Arnberg, N. (2005). CD46 is a cellular receptor for all species B adenoviruses except types 3 and 7. Journal of Virology, 79(22), 14429-14436
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, p. 14429-14436Article 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: 2018-06-09Bibliographically approved
Segerman, A., Atkinson, J. P., Marttila, M., Dennerquist, V., Wadell, G. & Arnberg, N. (2003). Adenovirus type 11 uses CD46 as a cellular receptor. Journal of Virology, 77(17), 9183-9191
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, E-ISSN 1098-5514, Vol. 77, no 17, p. 9183-9191Article 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: 2018-06-09Bibliographically approved
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