Inositol 1, 4, 5‐trisphosphate receptor regulates replication, differentiation, infectivity and virulence of the parasitic protist Trypanosoma cruzi. Issue 6 (4th February 2013)

• Record Type: Journal Article
• Authors: Hashimoto, Muneaki; Enomoto, Masahiro; Morales, Jorge; Kurebayashi, Nagomi; Sakurai, Takashi; Hashimoto, Tetsuo; Nara, Takeshi; Mikoshiba, Katsuhiko
• Is Part Of: Molecular microbiology. Volume 87:Issue 6(2013)
• Page Start: 1133
• Page End: 1150
• Publication Date: 2013-02-04
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.12155
• Languages: English
• ISSNs: 0950-382X

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>In animals, inositol 1, 4, 5‐trisphosphate receptors (IP<sub>3</sub>Rs) are ion channels that play a pivotal role in many biological processes by mediating Ca<sup>2+</sup> release from the endoplasmic reticulum. Here, we report the identification and characterization of a novel IP<sub>3</sub>R in the parasitic protist, <italic>Trypanosoma cruzi</italic>, the pathogen responsible for Chagas disease. DT40 cells lacking endogenous <italic>IP<sub>3</sub>R</italic> genes expressing <italic>T. cruzi</italic> IP<sub>3</sub>R (TcIP<sub>3</sub>R) exhibited IP<sub>3</sub>‐mediated Ca<sup>2+</sup> release from the ER, and demonstrated receptor binding to IP<sub>3</sub>. TcIP<sub>3</sub>R was expressed throughout the parasite life cycle but the expression level was much lower in bloodstream trypomastigotes than in intracellular amastigotes or epimastigotes. Disruption of two of the three <italic>TcIP<sub>3</sub>R</italic> gene loci led to the death of the parasite, suggesting that IP<sub>3</sub>R is essential for <italic>T. cruzi</italic>. Parasites expressing reduced or increased levels of TcIP<sub>3</sub>R displayed defects in growth, transformation and infectivity, indicating that TcIP<sub>3</sub>R is an important regulator of the parasite's life cycle. Furthermore, mice infected with <italic>T. cruzi</italic> expressing reduced levels of TcIP<sub>3</sub>R exhibited a reduction of disease symptoms, indicating that TcIP<sub>3</sub>R is an important virulence factor. Combined with the fact that the primary structure of TcIP<sub>3</sub>R has low similarity to that of mammalian IP<sub>3</sub>Rs, TcIP<sub>3</sub>R is a promising drug target for Chagas disease.</p> </abstract>