Fellowship Robert Molestina: Manipulation of the Host NF-Kappa B Pathway by the Opportunistic Pathogen Toxoplasma Gondii

  • Molestina, Robert (PI)

Grants and Contracts Details

Description

Toxoplasma gondii is an obligate intracellular protozoan parasite, which causes opportunistic disease in immunodeficient individuals and congenital disease in newborns. T. gondii is widely regarded as one of the most successful parasites on earth because of its broad host range and capability to establish an asymptomatic life-long chronic infection in immunocompetent populations. One of the strategies used by T. gondii to avoid destruction by the infected host cell is the inhibition of apoptosis. Studies performed by the candidate have shown that T. gondii induces a survival response in infected cells via NF-kappa B-dependent up-regulation of anti-apoptotic genes. Remarkably, activation of the NF-kappa B pathway by T. gondii occurs through an unconventional mechanism, which is independent of the host I-kappa B kinase (IKK). In addition, the evidence suggests the presence of a parasite-derived factor(s) capable of hijacking and phosphorylating I-kappa B. Identification of this factor(s) would provide insight into the modulation of host cell signaling events by Toxoplasma and reveal potential therapeutic targets. The proposed studies in this proposal will apply biochemical and molecular genetic approaches to characterize the putative I-kappa B kinase activity in T. gondii and address the following hypothesis: "Toxoplasma gondii manipulates the NF-kappa B pathway of the host cell by recruiting and phosphorylating I-kappa B via a parasite encoded factor(s) that can function autonomously from host IKK." To fulfill this hypothesis, the applicant will: (1) determine the activity of a parasite kinase capable of phosphorylating I-kappa B in subcellular fractions of T. gondii; and (2) identify protein candidates in T. gondii with I-kappa B kinase activity by proteomic and genomic analyses.
StatusFinished
Effective start/end date9/1/038/31/05

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