Heterozygosity for Crohn's Disease Risk Allele of ATG16L1 Protects against Bacterial Infection
Yao, X.; Rudensky, E.; Martin, P. K.; Zwack, E. E.; He, Z.; Furtado, G. C.; Lira, S. A.; Torres, V. J.; Shopsin, B.; Cadwell, K.
Show abstract
The T300A substitution in ATG16L1 associated with Crohns Disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300Adisplayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence. One-Sentence SummaryHeterozygosity of Crohns diseases risk variant ATG16L1 T300A confers protection against bacterial infections.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- A neutrophil-B-cell axis governs disease tolerance during sepsis via Cxcr4 96%
- A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation 95%
- Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells 95%
Similar papers in this journal
- CXCR6 promotes dermal CD8+ T cell survival and transition to long-term tissue residence 95%
- HOIL1 regulates group 3 innate lymphoid cell numbers in the colon and protects against systemic dissemination, colonic ulceration, and lethality from Citrobacter rodentium infection 95%
- Ubiquitin specific protease 1 expression and function in T cell immunity 95%
Similar papers in this journal
- Distinct Colitis-Associated Macrophages Drive NOD2-Dependent Bacterial Sensing and Gut Homeostasis 96%
- Inflammatory ER Stress Responses Dictate the Immunopathogenic Progression of Systemic Candidiasis 96%
- A20's Linear Ubiquitin Binding Motif Restrains Pathogenic Activation of TH17/22 cells and IL-22 Driven Enteritis 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.