title: Haemophilus ducreyi targets Src family protein tyrosine kinases to inhibit phagocytic signaling.
abstract: Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, has been shown to inhibit phagocytosis of both itself and secondary targets in vitro. Immunodepletion of LspA proteins from H. ducreyi culture supernatant fluid abolished this inhibitory effect, indicating that the LspA proteins are necessary for the inhibition of phagocytosis by H. ducreyi. Fluorescence microscopy revealed that macrophages incubated with wild-type H. ducreyi, but not with a lspA1 lspA2 mutant, were unable to complete development of the phagocytic cup around immunoglobulin G-opsonized targets. Examination of the phosphotyrosine protein profiles of these two sets of macrophages showed that those incubated with wild-type H. ducreyi had greatly reduced phosphorylation levels of proteins in the 50-to-60-kDa range. Subsequent experiments revealed reductions in the catalytic activities of both Lyn and Hck, two members of the Src family of protein tyrosine kinases that are known to be involved in the proximal signaling steps of Fcgamma receptor-mediated phagocytosis. Additional experiments confirmed reductions in the levels of both active Lyn and active Hck in three different immune cell lines, but not in HeLa cells, exposed to wild-type H. ducreyi. This is the first example of a bacterial pathogen that suppresses Src family protein tyrosine kinase activity to subvert phagocytic signaling in hostcells.
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9048, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
authors.forename: Merja
authors.initials: M
authors.lastname: Vakevainen
authors.forename: Kaiping
authors.initials: K
authors.lastname: Deng
authors.forename: Jo L
authors.initials: JL
authors.lastname: Latimer
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Young
authors.forename: Nicolai S C
authors.initials: NS
authors.lastname: van Oers
authors.forename: Steven
authors.initials: S
authors.lastname: Greenberg
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D002602:Chancroid / Q000201:enzymology / Q000276:immunology; D006191:Haemophilus ducreyi / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D037102:Lectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D009154:Mutation; D010587:Phagocytosis; D010750:Phosphoproteins / Q000378:metabolism; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors*; D017452:Receptors, IgG / Q000276:immunology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D037102:Lectins; C115859:LspA1 protein, Haemophilus ducreyi; C115860:LspA2 protein, Haemophilus ducreyi; D010750:Phosphoproteins; D017452:Receptors, IgG; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases