title: Pseudomonas aeruginosa disrupts Caenorhabditis elegans iron homeostasis, causing a hypoxic response and death.
abstract: The opportunistic pathogen Pseudomonas aeruginosa causes serious human infections, but effective treatments and the mechanisms mediating pathogenesis remain elusive. Caenorhabditis elegans shares innate immune pathways with humans, making it invaluable to investigate infection. To determine how P. aeruginosa disrupts host biology, we studied how P. aeruginosa kills C. elegans in a liquid-based pathogenesis model. We found that P. aeruginosa-mediated killing does not require quorum-sensing pathways or host colonization. A chemical genetic screen revealed that iron chelators alleviate P. aeruginosa-mediated killing. Consistent with a role for iron in P. aeruginosa pathogenesis, the bacterial siderophore pyoverdin was required for virulence and was sufficient to induce a hypoxic response and death in the absence of bacteria. Loss of the C. elegans hypoxia-inducing factor HIF-1, which regulates iron homeostasis, exacerbated P. aeruginosa pathogenesis, further linking hypoxia and killing. As pyoverdin is indispensable for virulence in mice, pyoverdin-mediated hypoxia is likely to be relevant in human pathogenesis.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Kirienko
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kirienko
authors.forename: Jonah
authors.initials: J
authors.lastname: Larkins-Ford
authors.forename: Carolina
authors.initials: C
authors.lastname: Wählby
authors.forename: Gary
authors.initials: G
authors.lastname: Ruvkun
authors.forename: Frederick M
authors.initials: FM
authors.lastname: Ausubel
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D000860:Hypoxia / Q000382:microbiology; D007501:Iron / Q000276:immunology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics / Q000276:immunology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014774:Virulence / Q000235:genetics / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; C541178:HIF-1 protein, C elegans; D014157:Transcription Factors; D037521:Virulence Factors; D007501:Iron