title: Coxsackievirus infection of the pancreas: evaluation of receptor expression, pathogenesis, and immunopathology.
abstract: Coxsackievirus type B (CVB) infection of the pancreas induces a massive cellular infiltrate composed of natural killer cells, T cells, and macrophages and leads to the destruction of exocrine tissue. The physiological manifestations of pancreatic CVB infection are correlated with viral tropism; the virus infects acinar cells but spares the islets of Langerhans. Here we evaluate the mechanisms underlying pancreatic inflammation and destruction and identify the determinants of viral tropism. T-cell-mediated immunopathology has been invoked, along with direct virus-mediated cytopathicity, to explain certain aspects of CVB-induced pancreatic disease. However, we show here that in the pancreas, the extent of inflammation and tissue destruction appears unaltered in the absence of the cytolytic protein perforin; these findings exclude any requirement for perforin-mediated lysis by natural killer cells or cytotoxic T cells in CVB3-induced pancreatic damage. Furthermore, perforin-mediated cytotoxic T-cell activity does not contribute to the control of CVB infection in this organ. In addition, we demonstrate that the recently identified coxsackie-adenovirus receptor is expressed at high levels in acinar cells but is barely detectable in islets, which is consistent with its being a major determinant of virus tropism and, therefore, of disease. However, further studies using various cell lines of pancreatic origin reveal secondary determinants of virus tropism.
authors.affiliation: Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: I
authors.initials: I
authors.lastname: Mena
authors.forename: C
authors.initials: C
authors.lastname: Fischer
authors.forename: J R
authors.initials: JR
authors.lastname: Gebhard
authors.forename: C M
authors.initials: CM
authors.lastname: Perry
authors.forename: S
authors.initials: S
authors.lastname: Harkins
authors.forename: J L
authors.initials: JL
authors.lastname: Whitton
mesh_terms: D000818:Animals; D018958:CD55 Antigens / Q000235:genetics; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D029822:Enterovirus B, Human / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000166:cytology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012367:RNA, Viral / Q000096:biosynthesis; D011991:Receptors, Virus / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014018:Tissue Distribution; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018958:CD55 Antigens; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012367:RNA, Viral; D011991:Receptors, Virus; D054353:Perforin