Trypanosoma cruzi antigen that interacts with the beta1-adrenergic receptor and modifies myocardial contractile activity.
Previously, we have demonstrated that plasma membranes from the parasite Trypanosoma cruzi (T. cruzi) recognize and adhere to host cells through parasite surface attachment molecules that have affinity for beta(1)-adrenergic receptors (beta(1)-ARs) on target organs. In this report we identify a parasite protein that not only interacts with beta(1)-ARs, but also displays beta-agonist-like activity. We demonstrate that a recombinant maltose binding protein fusion of Tc13 Tul (MBP-Tc13 Tul), a member of the T. cruzi antigen 13 family of surface antigen proteins, competes for binding sites with the beta-adrenergic receptor antagonist [125I]-CYP on membranes purified both from CHO cells expressing human beta(1)-ARs and from rat atria. The competition is prevented by pre-treating MBP-Tc13 Tul with antibodies directed against the EPKSA repeat domain of Tc13 Tul, implicating this portion of the molecule in binding to the beta(1)-AR. Furthermore, MBP-Tc13 Tul activates rat myocardial beta(1)-ARs, resulting in synthesis of cyclic adenosine monophosphate (cAMP) and an increase in cardiac contractility. These biological effects are selectively suppressed by the beta(1)-AR antagonist atenolol, by a synthetic peptide corresponding to the second extracellular loop of the human beta(1)-AR, and by the anti-EPKSA repeat antibodies. These results imply that the Tc13 Tul cell-surface antigen of T. cruzi plays a central role in misregulating the beta(1)-AR following parasite infection, and may be a causative factor of dysautonomic syndrome described in Chagas' disease.
Joensen
Lilian
L
Argentine National Parasitology Institute "Dr. Mario Fatala Chaben", ANLIS "Dr. Carlos G. Malbrán", University of Buenos Aires, Buenos Aires, Argentina.
Borda
Enri
E
Kohout
Trudy
T
Perry
Stephen
S
García
Gabriela
G
Sterin-Borda
Leonor
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000953:Antigens, Protozoan / Q000378:metabolism* / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity
D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D009124:Muscle Proteins; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D001262:Atenolol; D011433:Propranolol; D000242:Cyclic AMP; D007545:Isoproterenol