title: Pilus phase variation switches gonococcal adherence to invasion by caveolin-1-dependent host cell signaling.
abstract: Many pathogenic bacteria cause local infections but occasionally invade into the blood stream, often with fatal outcome. Very little is known about the mechanism underlying the switch from local to invasive infection. In the case of Neisseria gonorrhoeae, phase variable type 4 pili (T4P) stabilize local infection by mediating microcolony formation and inducing anti-invasive signals. Outer membrane porin PorB(IA), in contrast, is associated with disseminated infection and facilitates the efficient invasion of gonococci into host cells. Here we demonstrate that loss of pili by natural pilus phase variation is a prerequisite for the transition from local to invasive infection. Unexpectedly, both T4P-mediated inhibition of invasion and PorB(IA)-triggered invasion utilize membrane rafts and signaling pathways that depend on caveolin-1-Y14 phosphorylation (Cav1-pY14). We identified p85 regulatory subunit of PI3 kinase (PI3K) and phospholipase Cγ1 as new, exclusive and essential interaction partners for Cav1-pY14 in the course of PorBIA-induced invasion. Active PI3K induces the uptake of gonococci via a new invasion pathway involving protein kinase D1. Our data describe a novel route of bacterial entry into epithelial cells and offer the first mechanistic insight into the switch from local to invasive gonococcal infection.
authors.affiliation: Microbiology, University of Würzburg Biocenter, Würzburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Faulstich
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Böttcher
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
authors.forename: Martin
authors.initials: M
authors.lastname: Fraunholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Rudel
mesh_terms: D001422:Bacterial Adhesion; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000378:metabolism*; D006069:Gonorrhea / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D009344:Neisseria gonorrhoeae / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051242:Caveolin 1; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D011493:Protein Kinase C; C495540:CAV1 protein, human; C089212:protein kinase D