title: Listeria monocytogenes exploits cystic fibrosis transmembrane conductance regulator (CFTR) to escape the phagosome.
abstract: Virulence of the intracellular pathogen Listeria monocytogenes (Listeria) requires escape from the phagosome into the host cytosol, where the bacteria replicate. Phagosomal escape is a multistep process characterized by perforation, which is dependent on the pore-forming toxin listeriolysin O (LLO), followed by rupture. The contribution of host factors to Listeria phagosomal escape is incompletely defined. Here we show that the cystic fibrosis transmembrane conductance regulator (CFTR) facilitates Listeria cytosolic entry. CFTR inhibition or mutation suppressed Listeria vacuolar escape in culture, and inhibition of CFTR in wild-type mice before oral inoculation of Listeria markedly decreased systemic infection. We provide evidence that high chloride concentrations may facilitate Listeria vacuolar escape by enhancing LLO oligomerization and lytic activity. We propose that CFTR transiently increases phagosomal chloride concentration after infection, potentiating LLO pore formation and vacuole lysis. Our studies suggest that Listeria exploits mechanisms of cellular ion homeostasis to escape the phagosome and emphasize host ion-channel function as a key parameter of bacterial virulence.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Radtke
authors.forename: Kelsi L
authors.initials: KL
authors.lastname: Anderson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davis
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: DiMagno
authors.forename: Joel A
authors.initials: JA
authors.lastname: Swanson
authors.forename: Mary X
authors.initials: MX
authors.lastname: O'Riordan
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000382:microbiology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D006460:Hemolysin Proteins / Q000737:chemistry / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006834:Hydrazines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008089:Listeria monocytogenes / Q000378:metabolism / Q000502:physiology*; D008088:Listeriosis / Q000235:genetics / Q000378:metabolism / Q000382:microbiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010588:Phagosomes / Q000382:microbiology*; D055503:Protein Multimerization; D053778:Thiazolidines / Q000494:pharmacology; D014617:Vacuoles / Q000382:microbiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001427:Bacterial Toxins; D001565:Benzoates; D002121:Calcium Channel Blockers; D002712:Chlorides; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D006834:Hydrazines; C548779:N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide; D053778:Thiazolidines; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C001209:fenamic acid; C038705:hlyA protein, Listeria monocytogenes; D005998:Glycine