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Genetic analysis of pathogenesis in Toxoplasma gondii
Author(s) -
Sibley L. David
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.270.1
Subject(s) - biology , transcription factor , microbiology and biotechnology , effector , toxoplasma gondii , chromatin , gene , stat1 , transcription (linguistics) , innate immune system , genetics , chromatin remodeling , signal transduction , receptor , antibody , linguistics , philosophy
Toxoplasma gondii is a widespread parasite of animals that also causes opportunistic infections in humans. Forward genetic mapping studies and comparative genomic analyses of diverse strains have collectively demonstrated that virulence is largely mediated by expansion of several families of secretory pathogenesis determinants (SPDs). Among these are secreted effectors that bind to host transcription factors to disrupt host gene expression. For example, the recently described Inhibitor of STAT1 Transcription (TgIST) blocks the effect of interferon gamma, which is normally mediated by this host transcription factor. TgIST is secreted across the parasitophorous vacuole by a parasite‐encoded export pathway on the vacuole membrane. Within the host cell, TgIST binds to active phosphorylated STAT1 homodimers that are found tightly bound to promoter elements in nucleus, yet paradoxically transcription is blocked. Biochemical studies revealed that TgIST works by recruiting the Nucleosome Remodeling and Repressive complex (NuRD), which modifies chromatin to suppress gene expression. TgIST is predicted to be a highly unstructured protein, suggesting it recognizes its binding partners through induced fit – a property shared by many transcriptional co‐factors. TgIST is conserved among all strains of T. gondii and it mediates repression of type I, II and III interferons, thus dampening immunity. These studies reveal the molecular mechanism of how SPDs mediate changes in host gene expression to block innate immunity and contribute to pathogenesis. Support or Funding Information Supported by grants from the NIH.