Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection

Abstract

Autophagy, a conserved pathway that delivers intracellular materials into lysosomes for degradation, is involved in development, aging, and a variety of diseases. Accumulating evidence demonstrates that autophagy plays a protective role against infectious diseases by diminishing intracellular pathogens, including bacteria, viruses, and parasites. However, the mechanism by which autophagy regulates innate immunity remains largely unknown. Here, we show that autophagy is involved in host defense against a pathogenic bacterium Pseudomonas aeruginosa in the metazoan Caenorhabditis elegans. P. aeruginosa infection induces autophagy via a conserved extracellular signal-regulated kinase (ERK). Intriguingly, impairment of autophagy does not influence the intestinal accumulation of P. aeruginosa, but instead induces intestinal necrosis. Inhibition of necrosis results in the survival of autophagy-deficient worms after P. aeruginosa infection. These findings reveal a previously unidentified role for autophagy in protection against necrosis triggered by pathogenic bacteria in C. elegans and implicate that such a function of autophagy may be conserved through the inflammatory response in diverse organisms.A utophagy, a well-conserved lysosomal pathway that involves the degradation of cytoplasmic components, plays important roles in a broad diversity of the biological processes, ranging from development, senescence, and lifespan extension, to cancer (1, 2). In addition, autophagy has a prominent role in resistance to bacterial, viral, and protozoan infection in metazoan organisms (3-6). Autophagy is unique in its capacity to sequester invading bacteria, and target these pathogens for lysosomal degradation, thus providing a mechanism for the elimination of intracellular microorganisms. For example, after the pathogenic bacterium Streptococcus pyogenes (group A Streptococcus) enters human epithelial cells, the bacterium in the cytoplasm is sequestered in autophagosome-like compartments and degraded upon fusion with lysosomes. In contrast, Streptococcus exits freely into the cytoplasm of autophagy-deficient Atg5 −/− cells that lack autophagic ability (3). In phagocytic cells, such as macrophages, Mycobacterium tuberculosis resides intracellularly in the phagosome and blocks phagolysosome biogenesis (4). Induction of autophagy by physiological or pharmacological factors promotes mycobacterial colocalization with the autophagosomes and results in a decreased viability of intracellular mycobacteria (4, 7). In addition to pathogen clearance, accumulating evidence suggests that autophagy is associated with other aspects of immunity and inflammation (8-11). For instance, lack of autophagy in macrophages results in the accumulation of dysfunctional mitochondria, which, in turn, promotes secretion of proinflammatory factors IL-1β and IL-18 (8, 10), suggesting that autophagy regulates inflammation responses by suppressing the secretion of immune mediators.The genetically tractable model host Caenorhabditis elegans provides a useful tool ...

Caenorhabditis elegans microRNAs of the let-7 family act in innate immune response circuits and confer robust developmental timing against pathogen stress

“…Even though we have shown that the p38 MAPK pathway and the let-7 targets lin-41 and hbl-1 are required for this phenotype, it is also possible that additional downstream stress response effectors, such as skn-1 (27), could mediate the regulation for pathogen resistance by let-7-Fam miRNAs. Predicted targets of let-7-Fam miRNAs include components of several pathways involved in pathogen resistance, including the p38 MAPK pathway, the unfolded protein response pathway, the oxidative stress response pathway, and the autophagy pathway (27,32,48,49). We propose that let-7-Fam miRNAs could function during normal, unstressed development to dampen several stress response pathways, and that under stress conditions, such as P. aeruginosa infection, the down-regulation of let-7-Fam miRNA activity reported here would broadly augment the worm's stress response.…”

Microbial pathogenesis and host defense in the nematode C. elegans

“…These authors found a similar role for TFEB-1 in response to S. aureus infections in mammalian cells. An unusual role for autophagy in defense was shown by Zou et al, who demonstrated that autophagy activation prevents necrosis, and provides defense against P. aeruginosa infection [57]. Interestingly, autophagy did not reduce pathogen load (i.e.…”

Emerging strategies to effectively target autophagy in cancer

“…The impact autophagy has on human health and disease are far and wide, with reports demonstrating important functions in bacterial 1 and viral infections, 2 suppression of inflammation, 3 adaptive immune responses 4 and immunosurveillance, 5 neurodegeneration, 6 heart disease 7 and cancer. 8 Aberrant autophagic activity is an emerging hallmark of cancer, 9 serving a critical function in the pathogenesis, survival and response to therapy in a growing number of cancers.…”