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      Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11, and 14

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          Abstract

          We have identified desmoglein 2 (DSG2) as the primary high-affinity receptor used by adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14. These serotypes represent important human pathogens causing respiratory tract infections. In epithelial cells, adenovirus binding to DSG2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This improves access to receptors, e.g. CD46 and Her2/ neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDd), formed by viral penton and fiber in excess during viral replication, can trigger DSG2-mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDd. Our findings shed light on adenovirus biology and pathogenesis and have implications for cancer therapy.

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          Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5.

          J M Bergelson, J. A. Cunningham, G Droguett … (1997)
          A complementary DNA clone has been isolated that encodes a coxsackievirus and adenovirus receptor (CAR). When transfected with CAR complementary DNA, nonpermissive hamster cells became susceptible to coxsackie B virus attachment and infection. Furthermore, consistent with previous studies demonstrating that adenovirus infection depends on attachment of a viral fiber to the target cell, CAR-transfected hamster cells bound adenovirus in a fiber-dependent fashion and showed a 100-fold increase in susceptibility to virus-mediated gene transfer. Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
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            CD46 is a cellular receptor for group B adenoviruses.

            Anuj Gaggar, Dmitry Shayakhmetov, Andre Lieber (2003)
            Group B adenoviruses, a subgenus of human Adenoviridae, are associated with a variety of often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients. Recently, group B adenovirus derivatives have gained interest as attractive gene therapy vectors because they can transduce target tissues, such as hematopoietic stem cells, dendritic cells and malignant tumor cells, that are refractory to infection by commonly used adenoviral vectors. Whereas many adenoviruses infect cells through the coxsackievirus and adenovirus receptor (CAR), group B adenoviruses use an alternate, as-yet-unidentified cellular attachment receptor. Using mass spectrometric analysis of proteins interacting with a group B fiber, we identified human CD46 as a cellular attachment receptor for most group B adenoviruses. We show that ectopic expression of human CD46 rendered nonhuman cells susceptible to infection with group B viruses in vitro and in vivo. In addition, both siRNA-mediated knockdown of CD46 and a soluble form of CD46 blocked infection of human cell lines and primary human cells. The discovery that group B adenoviruses use CD46, a ubiquitously expressed complement regulatory protein, as a cellular attachment receptor elucidates the diverse clinical manifestation of group B virus infections, and bears directly on the application of these vectors for gene therapy.
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              Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site.

              Jenny Bostrom, Shang-Fan Yu, David Kan … (2009)
              The interface between antibody and antigen is often depicted as a lock and key, suggesting that an antibody surface can accommodate only one antigen. Here, we describe an antibody with an antigen binding site that binds two distinct proteins with high affinity. We isolated a variant of Herceptin, a therapeutic monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), on the basis of its ability to simultaneously interact with vascular endothelial growth factor (VEGF). Crystallographic and mutagenesis studies revealed that distinct amino acids of this antibody, called bH1, engage HER2 and VEGF energetically, but there is extensive overlap between the antibody surface areas contacting the two antigens. An affinity-improved version of bH1 inhibits both HER2- and VEGF-mediated cell proliferation in vitro and tumor progression in mouse models. Such "two-in-one" antibodies challenge the monoclonal antibody paradigm of one binding site, one antigen. They could also provide new opportunities for antibody-based therapy.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 22 November 2010
                Publication date (Electronic): 12 December 2010
                Publication date (Print): January 2011
                Publication date PMC-release: 1 July 2011
                Volume: 17
                Issue: 1
                Pages: 96-104
                Affiliations
                [1 ]University of Washington, Division of Medical Genetics, Box 357720, Seattle, WA 98195
                [2 ]Cancer Gene Therapy Group, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland
                [3 ]University of Washington, Department of Neurology
                [4 ]Bogazici University, Department Molecular Biology and Genetics, Istanbul, Turkey
                [5 ]Loma Linda University, Department of Medicine, Division of Regenerative Medicine Loma, Linda, CA 92350
                [6 ]University of Nebraska Medical Center, Omaha, Nebaska
                [7 ]Fred Hutchinson Cancer Research Center, Seattle, WA
                [8 ]Unit of Virus Host Cell Interactions, Grenoble, France
                Author notes
                Contact: André Lieber, phone: (206) 221-3973, Fax: (206) 685-8675, lieber00@ 123456u.washington.edu
                Article
                Manuscript ID: nihpa251224
                DOI: 10.1038/nm.2270
                PMC ID: 3074512
                PubMed ID: 21151137
                SO-VID: 1f8d0a08-7c81-466c-848c-7e35aa0979ad
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Cancer Institute : NCI
                Award ID: R21 AI072774-02 ||AI
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA144057-08 ||CA
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA136487-03 ||CA
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA083636-11 ||CA
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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