Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signaling-regulated pathogen resistance

Abstract

A conserved insulin-like pathway modulates both aging and pathogen resistance in Caenorhabditis elegans. However, the specific innate effector functions that mediate this pathogen resistance are largely unknown. Autophagy, a lysosomal degradation pathway, plays a role in controlling intracellular bacterial pathogen infections in cultured cells, but less is known about its role at the organismal level. We examined the effects of autophagy gene inactivation on Salmonella enterica Serovar Typhimurium (Salmonella typhimurium) infection in 2 model organisms, Caenorhabditis elegans and Dictyostelium discoideum. In both organisms, genetic inactivation of the autophagy pathway increases bacterial intracellular replication, decreases animal lifespan, and results in apoptotic-independent death. In C. elegans, genetic knockdown of autophagy genes abrogates pathogen resistance conferred by a loss-of-function mutation, daf-2(e1370), in the insulin-like tyrosine kinase receptor or by overexpression of the DAF-16 FOXO transcription factor. Thus, autophagy genes play an essential role in host defense in vivo against an intracellular bacterial pathogen and mediate pathogen resistance in long-lived mutant nematodes.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…This may suggest that autophagy provides raw material for new macromolecular synthesis that requires the action of DAF‐16/FoxO, recycling this material into cell‐protective longevity proteins (Hansen et al ., 2008). In Salmonella ‐infected worms, inactivation of the autophagy pathway was shown to increase bacterial intracellular replication, reducing animal lifespan, culminating in an apoptotic‐independent death (Jia et al ., 2009). Mutation of DAF‐2 or overexpression of the DAF‐16/FoxO conferred pathogen resistance, which is precluded with the genetic knockdown of autophagy genes (Jia et al ., 2009).…”

“…In Salmonella ‐infected worms, inactivation of the autophagy pathway was shown to increase bacterial intracellular replication, reducing animal lifespan, culminating in an apoptotic‐independent death (Jia et al ., 2009). Mutation of DAF‐2 or overexpression of the DAF‐16/FoxO conferred pathogen resistance, which is precluded with the genetic knockdown of autophagy genes (Jia et al ., 2009). …”

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…85 Thus, a strong association between defective autophagy and impaired properties counteracting bacterial infections has been reported by numerous studies. 73,[86][87][88][89] However, a recent study has revealed a protective role of Atg16l1 deficiency against intestinal disease induced by the bacterial pathogen model, Citrobacter rodentium. This immunosuppressive role of ATG16L1 deficiency is dependent on the presence of NOD2 90 and adds to the complexity of the role of ATG16L1 in bacterial clearance.…”

Antimicrobial effectors in the nematode Caenorhabditis elegans : an outgroup to the Arthropoda

“…In C. elegans, autophagy is required for host defence against Salmonella enterica serovar Typhimurium [39,40], N. parisii and S. aureus [23], and mitophagy (the specific elimination of mitochondria by autophagy) for resistance to Pseudomonas aeruginosa [41]. Its contribution to defence against these four pathogens shows some variation, as explained in more detail in the following: (i) S. enterica, a facultative intracellular pathogen, invades the C. elegans intestinal epithelial cells only in worms in which the autophagy gene bec-1 (homologous to human BECN1) is silenced by RNAi.…”