title: Identification of a peptide-pheromone that enhances Listeria monocytogenes escape from host cell vacuoles.
abstract: Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol.
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Xayarath
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Francis
authors.initials: F
authors.lastname: Alonzo
authors.affiliation: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Freitag
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D057131:Immune Evasion; D008074:Lipoproteins / Q000235:genetics / Q000276:immunology*; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010454:Peptide Termination Factors / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D010675:Pheromones / Q000235:genetics / Q000276:immunology*; D014617:Vacuoles / Q000276:immunology* / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D010454:Peptide Termination Factors; D010455:Peptides; D010675:Pheromones; C545356:PrfA protein, Listeria monocytogenes
references.citation: Curr Opin Microbiol. 2011 Apr;14(2):118-27
references.pmid: 21388862
references.citation: Appl Environ Microbiol. 2007 Oct;73(19):6125-33
references.pmid: 17675424
references.citation: Infect Immun. 2010 Nov;78(11):4944-57
references.pmid: 20823208
references.citation: J Bacteriol. 2000 Sep;182(17):4926-33
references.pmid: 10940037
references.citation: FEMS Microbiol Rev. 2014 May;38(3):473-92
references.pmid: 24118108
references.citation: J Bacteriol. 2007 Jan;189(2):313-24
references.pmid: 17041050
references.citation: Trends Microbiol. 2002 Aug;10(8):361-4
references.pmid: 12160633
references.citation: Appl Environ Microbiol. 2005 Oct;71(10):5771-8
references.pmid: 16204487
references.citation: J Bacteriol. 2004 Sep;186(18):6265-76
references.pmid: 15342597
references.citation: Cell Microbiol. 2006 Jan;8(1):107-19
references.pmid: 16367870
references.citation: Infect Immun. 1999 Jul;67(7):3512-7
references.pmid: 10377133
references.citation: Mol Microbiol. 2009 Mar;71(5):1177-89
references.pmid: 19154329
references.citation: PLoS One. 2011;6(8):e23502
references.pmid: 21858145
references.citation: Mol Microbiol. 1990 Jun;4(6):895-904
references.pmid: 2120541
references.citation: J Biol Chem. 2014 Aug 8;289(32):22427-36
references.pmid: 24958729
references.citation: Infect Immun. 2002 Feb;70(2):716-23
references.pmid: 11796604
references.citation: Infect Immun. 2009 Jul;77(7):2612-23
references.pmid: 19451247
references.citation: MMWR Morb Mortal Wkly Rep. 2013 Jun 7;62(22):448-52
references.pmid: 23739339
references.citation: Epidemiol Infect. 2006 Aug;134(4):744-51
references.pmid: 16318652
references.citation: J Bacteriol. 1993 Feb;175(4):1008-18
references.pmid: 8432694
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11140-4
references.pmid: 7479953
references.citation: Infect Immun. 2007 Dec;75(12):5886-97
references.pmid: 17938228
references.citation: Infect Immun. 2003 Aug;71(8):4463-71
references.pmid: 12874326
references.citation: Infect Immun. 2000 May;68(5):2579-86
references.pmid: 10768947
references.citation: Plasmid. 2007 Nov;58(3):205-27
references.pmid: 17590438
references.citation: Mol Microbiol. 2004 Jun;52(6):1553-65
references.pmid: 15186408
references.citation: Annu Rev Microbiol. 2006;60:451-75
references.pmid: 16771651
references.citation: Microbes Infect. 2007 Aug;9(10):1216-25
references.pmid: 17720601
references.citation: Infect Immun. 1994 Dec;62(12):5608-13
references.pmid: 7960143
references.citation: Future Microbiol. 2006 Jun;1(1):89-101
references.pmid: 17661688
references.citation: J Proteomics. 2013 Mar 27;80:183-95
references.pmid: 23291529
references.citation: J Cell Biol. 2002 Aug 5;158(3):409-14
references.pmid: 12163465
references.citation: J Bacteriol. 2007 Feb;189(4):1399-406
references.pmid: 17098891
references.citation: Annu Rev Genet. 1995;29:477-508
references.pmid: 8825484
references.citation: Anim Health Res Rev. 2005 Dec;6(2):211-7
references.pmid: 16583783
references.citation: Mol Microbiol. 2003 Jun;48(6):1537-51
references.pmid: 12791137
references.citation: Res Microbiol. 2013 Jul-Aug;164(6):620-39
references.pmid: 23542405
references.citation: Infect Immun. 1999 Jan;67(1):131-9
references.pmid: 9864207
references.citation: N Engl J Med. 2013 Sep 5;369(10):944-53
references.pmid: 24004121
references.citation: Plasmid. 2002 Nov;48(3):193-201
references.pmid: 12460535
references.citation: FEBS Lett. 1984 Dec 3;178(1):97-100
references.pmid: 6437872
references.citation: Infect Immun. 2011 Feb;79(2):548-61
references.pmid: 20974828
references.citation: Adv Immunol. 2012;113:19-32
references.pmid: 22244577
references.citation: Mol Microbiol. 1991 Feb;5(2):367-72
references.pmid: 1645839
references.citation: Mol Microbiol. 2002 May;44(3):803-17
references.pmid: 11994160
references.citation: Plasmid. 1979 Jul;2(3):454-65
references.pmid: 113798
references.citation: Cell. 2012 Aug 17;150(4):792-802
references.pmid: 22901809
references.citation: FEMS Microbiol Rev. 2003 Dec;27(5):559-92
references.pmid: 14638413
references.citation: Mol Microbiol. 2000 Jan;35(2):312-23
references.pmid: 10652092
references.citation: Antimicrob Agents Chemother. 1993 Nov;37(11):2474-7
references.pmid: 8285637
references.citation: J Biol Chem. 1988 Oct 5;263(28):14574-8
references.pmid: 3139658
references.citation: Proc Natl Acad Sci U S A. 1978 Jul;75(7):3479-83
references.pmid: 98769
references.citation: Appl Environ Microbiol. 1995 Jan;61(1):226-33
references.pmid: 7887604
references.citation: Annu Rev Genet. 2008;42:541-64
references.pmid: 18713030
references.citation: Mol Microbiol. 2009 May;72(4):905-17
references.pmid: 19400789
references.citation: Cold Spring Harb Perspect Med. 2012 Nov;2(11). pii: a012427. doi: 10.1101/cshperspect.a012427
references.pmid: 23125205
references.citation: J Bacteriol. 2008 Feb;190(4):1172-83
references.pmid: 18083822
references.citation: Chem Rev. 2011 Jan 12;111(1):117-51
references.pmid: 21174435
references.citation: Microbes Infect. 2007 Aug;9(10):1196-207
references.pmid: 17764998
references.citation: Annu Rev Microbiol. 2004;58:587-610
references.pmid: 15487949
references.citation: J Bacteriol. 1998 Dec;180(24):6655-60
references.pmid: 9852011
references.citation: Appl Environ Microbiol. 2008 Jul;74(14):4491-7
references.pmid: 18502930
references.citation: CMAJ. 2008 Oct 7;179(8):795-7
references.pmid: 18787096
references.citation: Arch Microbiol. 1989;151(6):486-90
references.pmid: 2505719
references.citation: Antonie Van Leeuwenhoek. 2002 Aug;81(1-4):233-43
references.pmid: 12448722
references.citation: Mol Microbiol. 1994 Jul;13(1):141-51
references.pmid: 7984088
references.citation: Virulence. 2011 Sep-Oct;2(5):379-94
references.pmid: 21921683
references.citation: Trends Microbiol. 1997 Jul;5(7):272-6
references.pmid: 9234509
references.citation: Front Biosci. 2003 Jan 1;8:d32-45
references.pmid: 12456319
references.citation: BMC Microbiol. 2005;5:58
references.pmid: 16212653
references.citation: Microbiology. 2011 Nov;157(Pt 11):3138-49
references.pmid: 21835879
references.citation: Infect Immun. 1990 Nov;58(11):3770-8
references.pmid: 2172168
references.citation: Mol Microbiol. 2009 Nov;74(4):956-73
references.pmid: 19818015
references.citation: J Bacteriol. 1992 Feb;174(4):1293-8
references.pmid: 1735720
references.citation: Infect Immun. 2000 Sep;68(9):4900-6
references.pmid: 10948103
references.citation: Microbes Infect. 2007 Aug;9(10):1188-95
references.pmid: 17719818
references.citation: Infect Immun. 1995 Nov;63(11):4531-4
references.pmid: 7591098
references.citation: J Bacteriol. 2006 Apr;188(8):2875-84
references.pmid: 16585749
references.citation: PLoS Pathog. 2013 Jan;9(1):e1003131
references.pmid: 23382675
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(14):5522-6
references.pmid: 2501788
references.citation: Microb Pathog. 2008 Oct;45(4):273-81
references.pmid: 18675335
references.citation: J Bacteriol. 2002 Apr;184(7):1880-7
references.pmid: 11889094
references.citation: J Exp Med. 1991 Mar 1;173(3):751-4
references.pmid: 1847723
references.citation: Mol Microbiol. 2011 Jun;80(6):1530-48
references.pmid: 21545417
references.citation: Int J Med Microbiol. 2006 Apr;296(2-3):141-7
references.pmid: 16503196
references.citation: Nat Rev Microbiol. 2009 Sep;7(9):623-8
references.pmid: 19648949
references.citation: J Bacteriol. 1999 Oct;181(19):5915-21
references.pmid: 10498702
references.citation: FEMS Immunol Med Microbiol. 2008 Jul;53(2):151-65
references.pmid: 18462388
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12432-7
references.pmid: 14527997
references.citation: J Bacteriol. 1993 Aug;175(16):5260-4
references.pmid: 8349566
references.citation: Infect Immun. 1992 Jan;60(1):25-30
references.pmid: 1729187
references.citation: Microbes Infect. 2007 Aug;9(10):1236-43
references.pmid: 17720602
references.citation: J Bacteriol. 2004 Sep;186(17):5629-39
references.pmid: 15317767
references.citation: J Bacteriol. 2008 Jan;190(1):107-11
references.pmid: 17965168
references.citation: Appl Environ Microbiol. 2008 Jul;74(13):3921-34
references.pmid: 18441118
references.citation: Infect Immun. 2000 Dec;68(12):7069-77
references.pmid: 11083832
references.citation: Biochimie. 1992 Jul-Aug;74(7-8):705-11
references.pmid: 1391050
references.citation: J Immunol. 1987 Sep 15;139(6):2005-9
references.pmid: 3114382
references.citation: Foodborne Pathog Dis. 2006 Winter;3(4):316-8
references.pmid: 17199513
references.citation: Peptides. 2004 Sep;25(9):1377-88
references.pmid: 15374642
references.citation: J Bacteriol. 1997 Mar;179(5):1533-40
references.pmid: 9045810
references.citation: Microbes Infect. 2007 Aug;9(10):1176-87
references.pmid: 17720603
references.citation: Cell Microbiol. 2009 Mar;11(3):363-9
references.pmid: 19068097
references.citation: Infect Immun. 2005 Apr;73(4):1917-26
references.pmid: 15784531
references.citation: Appl Environ Microbiol. 1998 Mar;64(3):1059-65
references.pmid: 9501445
references.citation: Future Microbiol. 2012 Jul;7(7):839-52
references.pmid: 22827306
references.citation: Clin Infect Dis. 2006 Jan 1;42(1):29-36
references.pmid: 16323088
references.citation: Cell Microbiol. 2006 May;8(5):781-92
references.pmid: 16611227
references.citation: Microbiology. 2008 Nov;154(Pt 11):3579-89
references.pmid: 18957610
references.citation: J Exp Med. 1988 Apr 1;167(4):1459-71
references.pmid: 2833557
references.citation: J Bacteriol. 1987 Mar;169(3):1291-7
references.pmid: 3029033
references.citation: Trends Cell Biol. 2008 May;18(5):220-7
references.pmid: 18396046
references.citation: Protein Sci. 2013 Jul;22(7):870-82
references.pmid: 23649542
references.citation: Commun Integr Biol. 2009 Jul;2(4):371-4
references.pmid: 19721895