title: Neisseria gonorrhoeae-induced transactivation of EGFR enhances gonococcal invasion.
abstract: Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhoea, adheres to and invades into genital epithelial cells. Here, we investigate host components that are used by the bacteria for their entry into epithelial cells. We found that gonococcal microcolony formation on the surface of HEC-1-B cells disrupted the polarized, basolateral distribution of both epidermal growth factor receptor (EGFR) and ErbB2, a related family member, and induced their accumulation under the microcolonies at the apical membrane. Gonococcal infection increased EGFR and ErbB2 phosphorylation. The EGFR kinase inhibitor, AG1478, reduced gonococcal invasion by 80%, but had no effect on adherence or the recruitment of EGFR and ErbB2 to the microcolonies. Gonococcal inoculation upregulated the mRNA levels of several ligands of EGFR. Prevention of EGFR ligand shedding by blocking matrix metalloproteinase activation reduced gonococcal invasion without altering their adherence, while the addition of the EGFR ligand, HB-EGF, was able to restore invasion to 66% of control levels. These data indicate that N. gonorrhoeae modulates the activity and cellular distribution of host EGFR, facilitating their invasion. EGFR activation does not appear to be due to direct gonococcal binding to EGFR, but instead by its transactivation by gonococcal induced increases in EGFR ligands.
authors.affiliation: Department of Cell Biology & Molecular Genetics, and Maryland Pathogen Research Institute, University of Maryland, College Park, MD, USA.
authors.forename: Karen V
authors.initials: KV
authors.lastname: Swanson
authors.forename: J McLeod
authors.initials: JM
authors.lastname: Griffiss
authors.forename: Vonetta L
authors.initials: VL
authors.lastname: Edwards
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Stein
authors.forename: Wenxia
authors.initials: W
authors.lastname: Song
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology; D066246:ErbB Receptors / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D006801:Humans; D009344:Neisseria gonorrhoeae / Q000254:growth & development / Q000472:pathogenicity*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D015534:Trans-Activators; D037521:Virulence Factors; C512478:EGFR protein, human; C508053:ERBB2 protein, human