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Glycogen synthase kinase 3 inhibition controls Mycobacterium tuberculosis infection.
Peña-Díaz, Sandra; Chao, Joseph D; Rens, Celine; Haghdadi, Hasti; Zheng, Xingji; Flanagan, Keegan; Ko, Mary; Shapira, Tirosh; Richter, Adrian; Maestre-Batlle, Danay; Canseco, Julio Ortiz; Gutierrez, Maximiliano Gabriel; Duc, Khanh Dao; Pelech, Steven; Av-Gay, Yossef.
Afiliación
  • Peña-Díaz S; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
  • Chao JD; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Rens C; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Haghdadi H; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
  • Zheng X; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
  • Flanagan K; Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
  • Ko M; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Shapira T; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Richter A; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Maestre-Batlle D; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
  • Canseco JO; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • Gutierrez MG; Host-pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK.
  • Duc KD; Host-pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK.
  • Pelech S; Department of Mathematics, University of British Columbia, Vancouver, BC, Canada.
  • Av-Gay Y; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
iScience ; 27(8): 110555, 2024 Aug 16.
Article en En | MEDLINE | ID: mdl-39175770
ABSTRACT
Compounds targeting host control of infectious diseases provide an attractive alternative to antimicrobials. A phenotypic screen of a kinase library identified compounds targeting glycogen synthase kinase 3 as potent inhibitors of Mycobacterium tuberculosis (Mtb) intracellular growth in the human THP-1 cell line and primary human monocytes-derived macrophages (hMDM). CRISPR knockouts and siRNA silencing showed that GSK3 isoforms are needed for the growth of Mtb and that a selected compound, P-4423632 targets GSK3ß. GSK3 inhibition was associated with macrophage apoptosis governed by the Mtb secreted protein tyrosine phosphatase A (PtpA). Phospho-proteome analysis of macrophages response to infection revealed a wide array of host signaling and apoptosis pathways controlled by GSK3 and targeted by P-4423632. P-4423632 was additionally found to be active against other intracellular pathogens. Our findings strengthen the notion that targeting host signaling to promote the infected cell's innate antimicrobial capacity is a feasible and attractive host-directed therapy approach.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos