title: Treatment of coxsackievirus-B3-infected BALB/c mice with the soluble coxsackie adenovirus receptor CAR4/7 aggravates cardiac injury.
abstract: Coxsackie adenovirus receptor (CAR) is involved in immunological processes, and its soluble isoforms have antiviral effects on coxsackievirus B3 (CVB3) infection in vitro. We explored in this study the impact of CAR4/7, a soluble CAR isoform, on CVB3-induced myocarditis in BALB/c mice. BALB/c mice were treated daily with recombinant CAR4/7, beta-galactosidase (beta-Gal; as control protein) or buffer for 9 days. Half of each group was infected with CVB3 on day 3, and all mice were killed on day 9. Myocardial CVB3 titer, histology, and serology were analyzed. Treatment with CAR4/7 led to a significant reduction of myocardial CVB3 titer, whereas the application of beta-Gal had no detectable effect on the myocardial virus load. CAR4/7 application, however, resulted in increased myocardial inflammation and tissue damage in CVB3-infected hearts, whereas beta-Gal caused a degree of cardiac inflammation and injury similar to that in buffer-treated CVB3-infected control animals. CAR4/7 and beta-Gal treatment induced the production of antibodies against the respective antigens. CAR4/7-, but not beta-Gal-specific, virus-negative sera reacted against myocardial tissue and cellular membranous CAR, and significantly inhibited CVB3 infection in vitro. Thus, CAR4/7 suppressed CVB3 infection in vivo, supporting the concept of receptor analog in antiviral therapy. However, CAR4/7 treatment also leads to an aggravation of myocardial inflammation and injury most likely secondary to an autoimmune process.
authors.affiliation: Department of Cardiology and Pneumonology, Charité University of Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. andrea.doerner@charite.de
authors.forename: A
authors.initials: A
authors.lastname: Dörner
authors.forename: H-P
authors.initials: HP
authors.lastname: Grunert
authors.forename: V
authors.initials: V
authors.lastname: Lindig
authors.forename: K
authors.initials: K
authors.lastname: Chandrasekharan
authors.forename: H
authors.initials: H
authors.lastname: Fechner
authors.forename: K U
authors.initials: KU
authors.lastname: Knowlton
authors.forename: A
authors.initials: A
authors.lastname: Isik
authors.forename: M
authors.initials: M
authors.lastname: Pauschinger
authors.forename: H
authors.initials: H
authors.lastname: Zeichhardt
authors.forename: H-P
authors.initials: HP
authors.lastname: Schultheiss
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D003402:Creatine Kinase / Q000097:blood; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000254:growth & development; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000139:chemically induced / Q000473:pathology / Q000821:virology; D011897:Random Allocation; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000685:Serum Amyloid A Protein / Q000032:analysis; D012995:Solubility
chemical_list: D000998:Antiviral Agents; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007106:Immune Sera; D011991:Receptors, Virus; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D003402:Creatine Kinase