A Deficiency in the Autophagy Gene Atg16L1 Enhances Resistance to Enteric Bacterial Infection

• Published in: Cell host & microbe Vol. 14; no. 2; pp. 216 - 224
• Main Authors: Marchiando, Amanda M., Ramanan, Deepshika, Ding, Yi, Gomez, Luis E., Hubbard-Lucey, Vanessa M., Maurer, Katie, Wang, Caihong, Ziel, Joshua W., van Rooijen, Nico, Nuñez, Gabriel, Finlay, B. Brett, Mysorekar, Indira U., Cadwell, Ken
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.08.2013
• Subjects: Animals; autophagy; bacterial infections; Bacterial Load; Carrier Proteins - genetics; Carrier Proteins - immunology; Citrobacter rodentium; Citrobacter rodentium - immunology; Crohn disease; Disease Models, Animal; Enterobacteriaceae Infections - immunology; Enterobacteriaceae Infections - pathology; genes; immune response; intestinal microorganisms; intracellular signaling peptides and proteins; Mice; Mice, Knockout; mutants; pathogens; phenotype; protective effect; Severity of Illness Index; Survival Analysis
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2013.07.013

Polymorphisms in the essential autophagy gene Atg16L1 have been linked with susceptibility to Crohn’s disease, a major type of inflammatory bowel disease (IBD). Although the inability to control intestinal bacteria is thought to underlie IBD, the role of Atg16L1 during extracellular intestinal bacterial infections has not been sufficiently examined and compared to the function of other IBD susceptibility genes, such as Nod2, which encodes a cytosolic bacterial sensor. We find that Atg16L1 mutant mice are resistant to intestinal disease induced by the model bacterial pathogen Citrobacter rodentium. An Atg16L1 deficiency alters the intestinal environment to mediate an enhanced immune response that is dependent on monocytic cells, but this hyperimmune phenotype and its protective effects are lost in Atg16L1/Nod2 double-mutant mice. These results reveal an immunosuppressive function of Atg16L1 and suggest that gene variants affecting the autophagy pathway may have been evolutionarily maintained to protect against certain life-threatening infections. [Display omitted] •Atg16L1 mutant mice are highly resistant to Citrobacter rodentium infection•Atg16L1 deficiency leads to a hyperimmune transcriptional profile in the intestine•Monocytic cells mediate an enhanced innate immune response in Atg16L1-deficient mice•Deletion of Nod2 abrogates protection due to Atg16L1 mutation