title: Antisense oligonucleotides targeting parasite inositol 1,4,5-trisphosphate receptor inhibits mammalian host cell invasion by Trypanosoma cruzi.
abstract: Chagas disease is caused by an intracellular parasitic protist, Trypanosoma cruzi. As there are no highly effective drugs against this agent that also demonstrate low toxicity, there is an urgent need for development of new drugs to treat Chagas disease. We have previously demonstrated that the parasite inositol 1,4,5-trisphosphate receptor (TcIP3R) is crucial for invasion of the mammalian host cell by T. cruzi. Here, we report that TcIP3R is a short-lived protein and that its expression is significantly suppressed in trypomastigotes. Treatment of trypomastigotes, an infective stage of T. cruzi, with antisense oligonucleotides specific to TcIP3R deceased TcIP3R protein levels and impaired trypomastigote invasion of host cells. Due to the resulting instability and very low expression level of TcIP3R in trypomastigotes indicates that TcIP3R is a promising target for antisense therapy in Chagas disease.
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nara
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hirawake
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Jorge
authors.initials: J
authors.lastname: Morales
authors.affiliation: Division of Signaling Biology, Ontario Cancer Institute, Toronto, ON, Canada M5G 1L7.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Enomoto
authors.affiliation: 1] Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama 351-0198, Japan [2] Calcium Oscillation Project, International Cooperative Research Project and Solution-Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015316:Genetic Therapy / Q000379:methods; D006367:HeLa Cells; D006790:Host-Parasite Interactions / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity* / Q000502:physiology*
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D016376:Oligonucleotides, Antisense; D015544:Inositol 1,4,5-Trisphosphate