Hypoxia and the Hypoxic Response Pathway Protect against Pore-Forming Toxins in C. elegans

Article Article scientifique Article Hypoxia and the Hypoxic Response Pathway Protect against Pore-Forming Toxins in C. elegans eng 2009 author Bellier Audrey 723370 author Chen Chang-Shi author Kao Cheng-Yuan author Cinar Hediye N. author Aroian Raffi V. e1000689 10.1371/journal.ppat.1000689 1553-7366 http://dx.plos.org/10.1371/journal.ppat.1000689 Pore-forming toxins (PFTs) are by far the most abundant bacterial protein toxins and are important for the virulence of many important pathogens. As such, cellular responses to PFTs critically modulate host-pathogen interactions. Although many cellular responses to PFTs have been recorded, little is understood about their relevance to pathological or defensive outcomes. To shed light on this important question, we have turned to the only genetic system for studying PFT-host interactions-Caenorhabditis elegans intoxication by Crystal (Cry) protein PFTs. We mutagenized and screened for C. elegans mutants resistant to a Cry PFT and recovered one mutant. Complementation, sequencing, transgenic rescue, and RNA interference data demonstrate that this mutant eliminates a gene normally involved in repression of the hypoxia (low oxygen response) pathway. We find that up-regulation of the C. elegans hypoxia pathway via the inactivation of three different genes that normally repress the pathway results in animals resistant to Cry PFTs. Conversely, mutation in the central activator of the hypoxia response, HIF-1, suppresses this resistance and can result in animals defective in PFT defenses. These results extend to a PFT that attacks mammals since up-regulation of the hypoxia pathway confers resistance to Vibrio cholerae cytolysin (VCC), whereas down-regulation confers hypersusceptibility. The hypoxia PFT defense pathway acts cell autonomously to protect the cells directly under attack and is different from other hypoxia pathway stress responses. Two of the downstream effectors of this pathway include the nuclear receptor nhr-57 and the unfolded protein response. In addition, the hypoxia pathway itself is induced by PFT, and low oxygen is protective against PFT intoxication. These results demonstrate that hypoxia and induction of the hypoxia response protect cells against PFTs, and that the cellular environment can be modulated via the hypoxia pathway to protect against the most prevalent class of weapons used by pathogenic bacteria. true PLOS Pathogens 5 12 3faced2b-326d-4c2f-ad4f-9f297d2cd5fa Article (Published version) Public journal.ppat.1000689(1).PDF 1362783 application/pdf CC0 openAccess

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Hypoxia and the Hypoxic Response Pathway Protect against Pore-Forming Toxins in C. elegans	PLOS Pathogens			2009	315	185

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