Molecular Basis of Human Toxoplasmosis

人类弓形虫病的分子基础

• 批准号: 10557864
• 负责人: L. David Sibley
• 金额: $ 66.82万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557864
• 关键词: Accidents; Acquired Immunodeficiency Syndrome; Animals; Antibiotics; Area; Attenuated; Back; Binding; Cell Death; Cell Nucleus; Cells; Central Nervous System; Chromatin; Chromatography; Complex; Cryoelectron Microscopy; Cyst; Frequencies; Funding; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; HIV/AIDS; Hematopoietic; High Prevalence; Highly Active Antiretroviral Therapy; Host Defense; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; In Vitro; Individual; Infection; Inflammatory; Interferon Type II; Interferon-beta; Interferons; Mediating; Mediator; Molecular; Natural Immunity; Natural Killer Cells; NuRD complex; Nutrient Depletion; Opportunistic Infections; Parasite Control; Parasites; Pathogenicity; Pathway interactions; Patients; Process; Production; Proteins; Repressor Proteins; Research Design; Risk; Rupture; STAT1 gene; Signal Transduction; T-Lymphocyte; Testing; Tissue Survival; Tissues; Toxoplasma gondii; Toxoplasmosis; Transcription Repressor; Up-Regulation; Vacuole; Virulence; X-Ray Crystallography; Zoonoses; acute infection; adaptive immunity; base; cell type; chronic infection; cytokine; differential expression; dimer; domain mapping; effective intervention; improved; in vivo; inhibitor; mutant; prevent; protein protein interaction; recruit; transcription factor; virtual

PROJECT SUMMARY/ABSTRACT Toxoplasma gondii is a common parasite of animals and frequent cause of accidental infection in humans. Acute infections are generally controlled by the immune response, but persistent chronic infection ensues due to survival of semi-dormant stages called bradyzoites that reside within tissue cysts. In immunocompromised patients, rupture of the tissue cysts releases bradyzoites that can convert back to rapidly replicating tachyzoites, a process that goes unrestricted due to decreased T-cell immunity. The potential for reactivation presents a continued risk to immunocompromised patients due to the fact that neither the immune system nor antibiotics can eradicate chronic infections. As such, there is still a need to understand fundamental mechanisms of pathogenicity in order to develop more effective interventions. One of the key mediators of innate and adaptive immunity to T. gondii is the production of interferons that activate cells to control the parasite through a variety of mechanisms including nutrient depletion, targeting the parasitophorous vacuole for destruction, or growth inhibition. As one of the world's most successful parasites, it is not surprising that T. gondii has developed active mechanisms to block these immune control pathways. Our studies seek to define the molecular bases of how T. gondii blocks or subverts interferon signaling to overcome host defenses. In the prior funding period, we identified a secretory parasite protein that traffics to the host nucleus where it binds to the transcription factor STAT1 and recruits a chromatin modifying complex to block gene expression induced by both type I (IFN-β) and type II (IFN-γ) interferons. Our prior studies demonstrate that the ability of the parasite to block type II IFN is primarily important in the acute infection while its ability to subvert type I IFN is key in the central nervous system during chronic infection. We have also recently identified a second secreted effector that also traffics to the host cell nucleus and blocks the type I IFN pathway. The proposed studies will explore the molecular mechanisms by which these effectors inhibit IFN signaling by bradyzoites and thus assure survival of tissue cysts that are responsible for chronic infection.

项目总结/文摘