Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation

Elise Burger, Alessandra Araujo, Américo López-Yglesias, Michael W. Rajala, Linda Geng, Beth Levine, Lora V. Hooper, Ezra Burstein, Felix Yarovinsky

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The protozoan parasite Toxoplasma gondii triggers severe small intestinal immunopathology characterized by IFN-γ- and intestinal microbiota-mediated inflammation, Paneth cell loss, and bacterial dysbiosis. Paneth cells are a prominent secretory epithelial cell type that resides at the base of intestinal crypts and releases antimicrobial peptides. We demonstrate that the microbiota triggers basal Paneth cell-specific autophagy via induction of IFN-γ, a known trigger of autophagy, to maintain intestinal homeostasis. Deletion of the autophagy protein Atg5 specifically in Paneth cells results in exaggerated intestinal inflammation characterized by complete destruction of the intestinal crypts resembling that seen in pan-epithelial Atg5-deficient mice. Additionally, lack of functional autophagy in Paneth cells within intestinal organoids and T. gondii-infected mice causes increased sensitivity to the proinflammatory cytokine TNF along with increased intestinal permeability, leading to exaggerated microbiota- and IFN-γ-dependent intestinal immunopathology. Thus, Atg5 expression in Paneth cells is essential for tissue protection against cytokine-mediated immunopathology during acute gastrointestinal infection. Autophagy is an essential cellular process in all cells. Burger et al. show that the microbiota drives autophagy predominantly in Paneth cells via basal induction of IFN-γ. A Paneth cell-restricted deficiency in autophagy results in the inability to control intestinal inflammation and acute mortality during T. gondii infection.

Original languageEnglish (US)
JournalCell Host and Microbe
DOIs
StateAccepted/In press - Jan 1 2018

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Paneth Cells
Autophagy
Toxoplasma
Inflammation
Microbiota
Dysbiosis
Organoids
Cytokines
Toxoplasmosis
Permeability
Parasites
Homeostasis
Epithelial Cells
Peptides
Mortality

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation. / Burger, Elise; Araujo, Alessandra; López-Yglesias, Américo; Rajala, Michael W.; Geng, Linda; Levine, Beth; Hooper, Lora V.; Burstein, Ezra; Yarovinsky, Felix.

In: Cell Host and Microbe, 01.01.2018.

Research output: Contribution to journalArticle

Burger, Elise ; Araujo, Alessandra ; López-Yglesias, Américo ; Rajala, Michael W. ; Geng, Linda ; Levine, Beth ; Hooper, Lora V. ; Burstein, Ezra ; Yarovinsky, Felix. / Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation. In: Cell Host and Microbe. 2018.
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