Heterozygosity for Crohn’s Disease Risk Allele ofATG16L1Protects against Bacterial Infection

Abstract

AbstractThe T300A substitution in ATG16L1 associated with Crohn’s 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 lethalSalmonella entericaTyphimurium infection. One copy ofAtg16L1T316Awas sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies ofAtg16L1T316Ainhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous forATG16L1T300Adisplayed 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 Crohn’s diseases risk variantATG16L1 T300Aconfers protection against bacterial infections.