title: A Yersinia pestis tat mutant is attenuated in bubonic and small-aerosol pneumonic challenge models of infection but not as attenuated by intranasal challenge.
abstract: Bacterial proteins destined for the Tat pathway are folded before crossing the inner membrane and are typically identified by an N-terminal signal peptide containing a twin arginine motif. Translocation by the Tat pathway is dependent on the products of genes which encode proteins possessing the binding site of the signal peptide and mediating the actual translocation event. In the fully virulent CO92 strain of Yersinia pestis, the tatA gene was deleted. The mutant was assayed for loss of virulence through various in vitro and in vivo assays. Deletion of the tatA gene resulted in several consequences for the mutant as compared to wild-type. Cell morphology of the mutant bacteria was altered and demonstrated a more elongated form. In addition, while cultures of the mutant strain were able to produce a biofilm, we observed a loss of adhesion of the mutant biofilm structure compared to the biofilm produced by the wild-type strain. Immuno-electron microscopy revealed a partial disruption of the F1 antigen on the surface of the mutant. The virulence of the ΔtatA mutant was assessed in various murine models of plague. The mutant was severely attenuated in the bubonic model with full virulence restored by complementation with the native gene. After small-particle aerosol challenge in a pneumonic model of infection, the mutant was also shown to be attenuated. In contrast, when mice were challenged intranasally with the mutant, very little difference in the LD50 was observed between wild-type and mutant strains. However, an increased time-to-death and delay in bacterial dissemination was observed in mice infected with the ΔtatA mutant as compared to the parent strain. Collectively, these findings demonstrate an essential role for the Tat pathway in the virulence of Y. pestis in bubonic and small-aerosol pneumonic infection but less important role for intranasal challenge.
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Bozue
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Cote
authors.affiliation: Pathology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Taylor
authors.initials: T
authors.lastname: Chance
authors.affiliation: Center for Genome Sciences, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kugelman
authors.affiliation: Office of Research Support, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kern
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Todd K
authors.initials: TK
authors.lastname: Kijek
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Jenkins
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Sherry
authors.initials: S
authors.lastname: Mou
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Krishna
authors.initials: K
authors.lastname: Moody
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Fritz
authors.affiliation: Pathology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Camenzind G
authors.initials: CG
authors.lastname: Robinson
authors.affiliation: Pathology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Bell
authors.affiliation: Bacteriology Division, The United States Army of Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Worsham
mesh_terms: D000336:Aerosols; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010930:Plague / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015010:Yersinia pestis / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D000336:Aerosols; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins
references.citation: Infect Immun. 2008 May;76(5):2025-36
references.pmid: 18347051
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10482-6
references.pmid: 16027357
references.citation: J Biol Chem. 2012 Mar 2;287(10):7335-44
references.pmid: 22190680
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13514-9
references.pmid: 16938880
references.citation: FEMS Microbiol Lett. 2012 Jul;332(2):113-21
references.pmid: 22537022
references.citation: FEMS Microbiol Lett. 2010 Jan;302(2):151-8
references.pmid: 19929966
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8097-101
references.pmid: 18523005
references.citation: Microb Pathog. 2011 Jun;50(6):314-21
references.pmid: 21320584
references.citation: J Med Microbiol. 2009 Jan;58(Pt 1):26-36
references.pmid: 19074650
references.citation: Infect Immun. 2011 Feb;79(2):644-52
references.pmid: 21115720
references.citation: J Bacteriol. 2008 May;190(9):3381-5
references.pmid: 18310330
references.citation: Biochem Biophys Res Commun. 2005 Jun 17;331(4):1413-20
references.pmid: 15883032
references.citation: Gene. 1990 Mar 1;87(1):133-7
references.pmid: 2332165
references.citation: J Bacteriol. 2003 Feb;185(4):1478-83
references.pmid: 12562823
references.citation: Infect Immun. 1977 Mar;15(3):972-7
references.pmid: 858647
references.citation: mBio. 2014 Jan 21;5(1):e01016-13
references.pmid: 24449753
references.citation: J Mol Biol. 2002 Oct 4;322(5):1135-46
references.pmid: 12367533
references.citation: Microbiology (Reading). 2008 Feb;154(Pt 2):584-592
references.pmid: 18227262
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17786-91
references.pmid: 16306265
references.citation: Infect Immun. 2009 May;77(5):1807-16
references.pmid: 19237527
references.citation: J Clin Microbiol. 1985 Jun;21(6):919-21
references.pmid: 2409104
references.citation: Vaccine. 2002 May 22;20(17-18):2206-14
references.pmid: 12009274
references.citation: J Biol Chem. 2000 Apr 21;275(16):11591-6
references.pmid: 10766774
references.citation: Am J Trop Med Hyg. 1990 Oct;43(4):389-96
references.pmid: 2240367
references.citation: Infect Immun. 2005 Apr;73(4):2020-32
references.pmid: 15784543
references.citation: Science. 2007 Jan 26;315(5811):509-13
references.pmid: 17255510
references.citation: Infect Immun. 1973 Dec;8(6):876-81
references.pmid: 4206343
references.citation: Infect Immun. 2007 Jan;75(1):429-42
references.pmid: 17074849
references.citation: Biochemistry. 2002 Nov 19;41(46):13690-7
references.pmid: 12427031
references.citation: Front Microbiol. 2010 Dec 29;1:141
references.pmid: 21772830
references.citation: Genome Res. 2003 Sep;13(9):2018-29
references.pmid: 12952873
references.citation: Infect Immun. 2005 Aug;73(8):5256-61
references.pmid: 16041052
references.citation: Am J Clin Pathol. 2002 Feb;117(2):205-9
references.pmid: 11863216
references.citation: Mol Plant Microbe Interact. 2006 Feb;19(2):200-12
references.pmid: 16529382
references.citation: Mol Microbiol. 1996 Nov;22(3):393-404
references.pmid: 8939424
references.citation: FEBS Lett. 2001 Oct 5;506(2):143-8
references.pmid: 11591389
references.citation: Arch Microbiol. 2009 Feb;191(2):163-70
references.pmid: 18998110
references.citation: Mol Microbiol. 1992 Sep;6(18):2693-704
references.pmid: 1447977
references.citation: Appl Microbiol. 1969 Nov;18(5):834-7
references.pmid: 5370459
references.citation: Mol Microbiol. 1998 Dec;30(5):965-78
references.pmid: 9988474
references.citation: Am J Trop Med Hyg. 1997 Apr;56(4):471-3
references.pmid: 9158060
references.citation: J Bacteriol. 2003 Feb;185(3):760-71
references.pmid: 12533451
references.citation: Appl Environ Microbiol. 2008 Dec;74(24):7507-13
references.pmid: 18931290
references.citation: J Bacteriol. 2014 Jan;196(2):407-16
references.pmid: 24214943
references.citation: PLoS One. 2010 Feb 16;5(2):e9225
references.pmid: 20169075
references.citation: Adv Exp Med Biol. 2003;529:129-31
references.pmid: 12756743
references.citation: Infect Immun. 2009 Dec;77(12):5449-57
references.pmid: 19786563
references.citation: Arch Pathol Lab Med. 1996 Feb;120(2):156-63
references.pmid: 8712895
references.citation: Mol Microbiol. 2002 Mar;43(6):1457-70
references.pmid: 11952898
references.citation: Infect Immun. 1991 Dec;59(12):4310-7
references.pmid: 1937792
references.citation: Gene. 1991 Apr;100:195-9
references.pmid: 2055470
references.citation: Am J Pathol. 2009 Mar;174(3):910-21
references.pmid: 19164505
references.citation: EMBO J. 2001 Dec 3;20(23):6735-41
references.pmid: 11726509
references.citation: Mol Microbiol. 2002 Mar;43(6):1555-64
references.pmid: 11952904
references.citation: Microb Pathog. 1991 Feb;10(2):87-91
references.pmid: 1890954
references.citation: J Bacteriol. 2005 Dec;187(24):8450-61
references.pmid: 16321949
references.citation: BMC Microbiol. 2005 Oct 07;5:58
references.pmid: 16212653
references.citation: Mol Microbiol. 1989 Oct;3(10):1455-9
references.pmid: 2693899
references.citation: Nature. 2001 Oct 4;413(6855):523-7
references.pmid: 11586360
references.citation: Contrib Microbiol Immunol. 1995;13:325-8
references.pmid: 8833864
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8312-7
references.pmid: 12034867
references.citation: Microb Pathog. 1997 Oct;23(4):211-23
references.pmid: 9344782
references.citation: BMC Microbiol. 2009 May 31;9:114
references.pmid: 19480715
references.citation: Clin Microbiol Rev. 1997 Jan;10(1):35-66
references.pmid: 8993858
references.citation: Microbes Infect. 2008 Oct;10(12-13):1398-404
references.pmid: 18762267
references.citation: Arch Pathol Lab Med. 1997 Aug;121(8):865-8
references.pmid: 9278616
references.citation: FEBS Lett. 2001 May 18;497(1):45-9
references.pmid: 11376660
references.citation: Mol Microbiol. 2000 Jan;35(2):260-74
references.pmid: 10652088
references.citation: Infect Immun. 2006 Mar;74(3):1768-76
references.pmid: 16495550
references.citation: J Bacteriol. 1991 Apr;173(8):2649-57
references.pmid: 1901573
references.citation: Int Arch Allergy Immunol. 2010;153(3):249-58
references.pmid: 20484923
references.citation: J Bacteriol. 1998 Mar;180(5):1207-14
references.pmid: 9495760
references.citation: Microbiology (Reading). 2011 Mar;157(Pt 3):805-818
references.pmid: 21088108
references.citation: Infect Immun. 1996 Nov;64(11):4580-5
references.pmid: 8890210
references.citation: Trends Microbiol. 2001 Oct;9(10):494-500
references.pmid: 11597451
references.citation: FEBS Lett. 1991 Jul 29;286(1-2):79-82
references.pmid: 1677900
references.citation: Infect Immun. 1993 Jan;61(1):13-22
references.pmid: 8418035
references.citation: Curr Microbiol. 2011 Apr;62(4):1193-9
references.pmid: 21170534
references.citation: PLoS One. 2009 Jul 17;4(7):e6281
references.pmid: 19609450
references.citation: J Biol Chem. 2000 Jun 2;275(22):16717-22
references.pmid: 10747959
references.citation: Infect Immun. 2009 Mar;77(3):1222-9
references.pmid: 19103769
references.citation: Contrib Microbiol Immunol. 1995;13:299-305
references.pmid: 8833858
references.citation: FEMS Immunol Med Microbiol. 1998 Jun;21(2):159-68
references.pmid: 9685006
references.citation: J Bacteriol. 1988 Sep;170(9):3967-77
references.pmid: 2842295
references.citation: FEBS Lett. 1992 Feb 3;297(1-2):77-80
references.pmid: 1551441
references.citation: Mol Microbiol. 2008 Sep;69(6):1349-57
references.pmid: 18643934
references.citation: Am J Trop Med Hyg. 1994 Jul;51(1):109-14
references.pmid: 8059908
references.citation: J Med Microbiol. 1995 Apr;42(4):264-8
references.pmid: 7707334
references.citation: Mol Microbiol. 1994 Aug;13(4):697-708
references.pmid: 7997181
references.citation: Clin Infect Dis. 1995 Oct;21 Suppl 2:S178-81
references.pmid: 8845449
references.citation: J Bacteriol. 2001 Jan;183(1):139-44
references.pmid: 11114910
references.citation: Infect Immun. 1998 Jun;66(6):2976-9
references.pmid: 9596775
references.citation: Mol Microbiol. 1999 Jun;32(5):961-76
references.pmid: 10361299