title: Effective Apical Infection of Differentiated Human Bronchial Epithelial Cells and Induction of Proinflammatory Chemokines by the Highly Pneumotropic Human Adenovirus Type 14p1.
abstract: BACKGROUND
  Only a few pneumotropic types of the human adenoviruses (e.g. type B14p1) cause severe lower respiratory tract infections like pneumonia and acute respiratory distress syndrome (ARDS) even in immunocompetent patients. By contrast, many other human adenovirus (HAdV) types (e.g. HAdV-C5) are associated mainly with upper respiratory tract infections. This is in accordance with a highly physiological cell culture system consisting of differentiated primary human bronchial epithelial cells which are little susceptible for apical HAdV-C5 infections.
  
  
  OBJECTIVE
  We hypothesized that a pneumotropic and highly pathogenic HAdV type infects differentiated human bronchial epithelial cells efficiently from the apical surface and also induces proinflammatory cytokines in order to establish ARDS and pneumonia. Therefore, the apical infection of differentiated primary human bronchial epithelial cells with the pneumotropic and virulent type HAdV-B14p1 was investigated in comparison to the less pneumotropic HAdV-C5 as a control.
  
  
  RESULTS
  Binding of HAdV-B14p1 to the apical surface of differentiated human bronchial epithelial cells and subsequent internalization of HAdV DNA was 10 fold higher (p<0.01) compared to the less-pneumotropic HAdV-C5 one hour after infection. Overall, the replication cycle of HAdV-B14p1 following apical infection and including apical release of infectious virus progeny was about 1000-fold more effective compared to the non-pneumotropic HAdV-C5 (p<0.001). HAdV-B14p1 infected cells expressed desmoglein 2 (DSG2), which has been described as potential receptor for HAdV-B14p1. Moreover, HAdV-B14p1 induced proinflammatory chemokines IP-10 and I-Tac as potential virulence factors. Interestingly, IP-10 has already been described as a marker for severe respiratory infections e.g. by influenza virus A H5N1.
  
  
  CONCLUSIONS
  The efficient "apical to apical" replication cycle of HAdV-B14p1 can promote endobronchial dissemination of the infection from the upper to the lower respiratory tract. Simultaneous induction of proinflammatory cytokines probably contributes to the high virulence of HAdV-B14p1.
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany; Heinrich-Pette-Institute, Department Viral Transformation, Hamburg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Lam
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Mirja
authors.initials: M
authors.lastname: Ramke
authors.affiliation: Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.affiliation: University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Laboratory, Universitäts Klinikum Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Schrepfer
authors.affiliation: Department of Dermatology, Hannover Medical School, Hannover, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Kopfnagel
authors.affiliation: Heinrich-Pette-Institute, Department Viral Transformation, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dobner
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Heim
mesh_terms: D000258:Adenovirus Infections, Human / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000260:Adenoviruses, Human / Q000502:physiology*; D001980:Bronchi / Q000473:pathology*; D002454:Cell Differentiation; D002469:Cell Separation; D018925:Chemokines / Q000378:metabolism*; D051301:Desmoglein 2 / Q000378:metabolism; D004847:Epithelial Cells / Q000821:virology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D014771:Virion / Q000378:metabolism
chemical_list: D018925:Chemokines; C495314:DSG2 protein, human; D051301:Desmoglein 2; D018836:Inflammation Mediators