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

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.

Systematic review: gastrointestinal infection and incident inflammatory bowel disease

“…Oral route of infection with Toxoplasma gondii in mice resulted in loss of tolerance to commensals and differentiation of microbiota‐specific T cells into inflammatory effector and memory cells, which were phenotypically and functionally consistent with pathogen‐specific T cells. These data suggest that during an acute GI infection, the immune response to commensals may parallel the response to pathogens 30,53 …”

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP 1/ IGF 2 BP 1

“…Pathway enrichment analysis for genes with differential translational efficiency revealed a significant representation of pathways linked to cell cycle, gene expression and RNA processing, post‐translational modification, autophagy, and metabolism (Fig B and Table EV1). These analyses (i) support the concept that IMP1 levels can globally affect mRNA abundance and translation efficiency, and (ii) compelled us to consider autophagy as a putative pathway underlying a role for IMP1 in colonic epithelial repair based upon evidence for autophagy as a protective mechanism in the gut .…”

“…*P < 0.05; **P < 0.01 by unpaired two-tailed t-test (for DSS weights, significance was determined using the Mann-Whitney test). Imp1 WT Imp1 IEC Imp1 WT Imp1 IEC Imp1 WT Imp1 IEC Imp1 WT Tumor size (mm) based upon evidence for autophagy as a protective mechanism in the gut [42][43][44][45][46][47].…”

Essential role of IFN-γ in T cell–associated intestinal inflammation

“…Paneth cell homeostasis is sensitive to proinflammatory conditions that induce Paneth cell depletion and may impair the ability of crypt ISCs to proliferate and regenerate the epithelial barrier. For example, loss of Paneth cells is associated with the onset of inflammation in graft-versus-host disease (GVHD) (9)(10)(11), during Toxoplasma gondii infection (12,13), and in autoimmune enteropathy (AIE) (14)(15)(16)(17). The subsequent reductions in mucosal defense mechanisms and the resulting dysbiosis exacerbate inflammation and may compromise tissue repair by disturbing the ISC crypt microenvironment.…”