Marko Marttila

Umeå University, Umeå, Västerbotten, Sweden

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Publications (9)45.41 Total impact

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    ABSTRACT: 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 μM) and Ad infectivity (IC(50) = 0.7 μM). 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.
    Journal of Medicinal Chemistry 08/2011; 54(19):6670-5. DOI:10.1021/jm200545m · 5.48 Impact Factor
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    ABSTRACT: 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.
    Virology 09/2010; 405(2):474-82. DOI:10.1016/j.virol.2010.06.026 · 3.28 Impact Factor
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    ABSTRACT: 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.
    Journal of Virology 12/2008; 83(2):673-86. DOI:10.1128/JVI.01967-08 · 4.65 Impact Factor
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    ABSTRACT: 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.
    Nature Structural & Molecular Biology 03/2007; 14(2):164-6. DOI:10.1038/nsmb1190 · 11.63 Impact Factor
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    ABSTRACT: 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.
    Journal of Virology 02/2007; 81(2):954-63. DOI:10.1128/JVI.01995-06 · 4.65 Impact Factor
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    ABSTRACT: Background: Adenoviruses of species A, B, C, D, E and F differ in tropism. In order to address the molecular determinants of adenovirus tropism the distribution of adenovirus receptors on cells of hematopoietic and endothelial origin, and the expression in these cells was assessed.Results: The receptors for species B adenoviruses were most abundantly expressed. CAR binding amino acid residues are not conserved in their fiber knobs consequently CAR can not be used as a receptor. Virions of Ad11p, Ad35 & Ad3 (species B) showed high- affinity to CD34(+) cells, Ad7, Ad11a (species B) and Ad37 (species D) showed intermediate affinity whereas Ad4 (species E), Ad5 (species C), Ad31 (species A) and Ad41 (species F) hardly bound to CD34 hematopoietic progenitor cells. Only species B and species D adenovirus were expressed in these cells. Based on DNA homology two groups are defined within species B. Ad3, 7, 16, 21 (B:1), and Ad11, 14, 34, 35 and 50 (B:2). Ad3 and Ad7 cause acute respiratory tract infections, whereas Ad11, 34 and 35 cause persistent infections of the urinary tract. We suggest two different receptors for species B adenoviruses: sBAR common to species B members and sB2AR unique for Ad11 and Ad35 members of species B:2. Ad11 virions blocked the binding of Ad3 or Ad7 species B to 70%, whereas Ad3 blocked the binding of Ad11 and Ad35 only partially 30%. sBAR is sensitive to trypsin and EDTA treatment of A549 cells or J82 cells whereas sB2AR is resistent. The binding of Ad3 and Ad7 was restored with Ca++. Non permissive chinese hamster ovary (CHO) cells were transfected with the BC1 or BC2 isoforms of CD46 – cDNA. Ad11 virions did but Ad5 virions did not bind to CD46 transfected CHO cells. Adenovirus 11 and 35 can attach and infect primary lymphocytes and monocytes but hexon expression in T- cells required prior activation, whereas neither Ad3, Ad7 nor Ad5 were expressed in the primary PBMCs. Assessment of the transduction ability of established hematopoietic cell lines by a species B vector revealed that Jurkat, U937 and K562 were more efficiently transduced than DG75 cells.EKC causing Ad37 (species D) uses 2-3 linked sialic acid as a primarily functional receptor. The structure of the fiber knob of Ad37 and Ad19p was resolved at 1.5-2Å by W. Burmeister using X-ray crystallography. The binding site for sialyl lactose was identified on the top of the knob close to the 3-fold axis of the trimer. NB Ad37 infects CD34+ cellsConclusion: Species B and D adenovirus using CD46 and 2-3- linked sialic acid as receptors, respectively, infected hematopoietic progenitor cells. Ad11 and Ad35 were more efficient than all other assessed adenoviruses.
    Molecular Therapy 05/2006; 13. DOI:10.1016/j.ymthe.2006.08.444 · 6.43 Impact Factor
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    ABSTRACT: 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.
    Journal of Virology 12/2005; 79(22):14429-36. DOI:10.1128/JVI.79.22.14429-14436.2005 · 4.65 Impact Factor
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    ABSTRACT: 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.
    Journal of Virology 10/2003; 77(17):9183-91. DOI:10.1128/JVI.77.17.9183-9191.2003 · 4.65 Impact Factor
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    Marko Marttila

Publication Stats

456 Citations
45.41 Total Impact Points

Institutions

  • 2007–2010
    • Umeå University
      • Department of Clinical Microbiology
      Umeå, Västerbotten, Sweden
  • 2008
    • Vanderbilt University
      Nashville, Michigan, United States
  • 2003–2005
    • Washington University in St. Louis
      • Division of Rheumatology
      San Luis, Missouri, United States