title: The hybrid histidine kinase Hk1 is part of a two-component system that is essential for survival of Borrelia burgdorferi in feeding Ixodes scapularis ticks.
abstract: Two-component systems (TCS) are principal mechanisms by which bacteria adapt to their surroundings. Borrelia burgdorferi encodes only two TCS. One is comprised of a histidine kinase, Hk2, and the response regulator Rrp2. While the contribution of Hk2 remains unclear, Rrp2 is part of a regulatory pathway involving the spirochete's alternate sigma factors, RpoN and RpoS. Genes within the Rrp2/RpoN/RpoS regulon function to promote tick transmission and early infection. The other TCS consists of a hybrid histidine kinase, Hk1, and the response regulator Rrp1. Hk1 is composed of two periplasmic sensor domains (D1 and D2), followed by conserved cytoplasmic histidine kinase core, REC, and Hpt domains. In addition to its REC domain, Rrp1 contains a GGDEF motif characteristic of diguanylate cyclases. To investigate the role of Hk1 during the enzootic cycle, we inactivated this gene in two virulent backgrounds. Extensive characterization of the resulting mutants revealed a dramatic phenotype whereby Hk1-deficient spirochetes are virulent in mice and able to migrate out of the bite site during feeding but are killed within the midgut following acquisition. We hypothesize that the phosphorelay between Hk1 and Rrp1 is initiated by the binding of feeding-specific ligand(s) to Hk1 sensor domain D1 and/or D2. Once activated, Rrp1 directs the synthesis of cyclic dimeric GMP (c-di-GMP), which, in turn, modulates the expression and/or activity of gene products required for survival within feeding ticks. In contrast to the Rrp2/RpoN/RpoS pathway, which is active only within feeding nymphs, the Hk1/Rrp1 TCS is essential for survival during both larval and nymphal blood meals.
authors: Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030-3715, USA. mcaima@up.uchc.edu
authors: Melissa J
authors: MJ
authors: Caimano
authors: Melisha R
authors: MR
authors: Kenedy
authors: Toru
authors: T
authors: Kairu
authors: Daniel C
authors: DC
authors: Desrosiers
authors: Michael
authors: M
authors: Harman
authors: Star
authors: S
authors: Dunham-Ems
authors: Darrin R
authors: DR
authors: Akins
authors: Utpal
authors: U
authors: Pal
authors: Justin D
authors: JD
authors: Radolf
references: Front Biosci (Landmark Ed). 2009 Jan 01;14:3051-63
references: 19273256
references: J Bacteriol. 2007 Mar;189(5):2139-44
references: 17158681
references: BMC Microbiol. 2005 Jun 14;5:35
references: 15955239
references: Infect Immun. 1998 Jun;66(6):2674-83
references: 9596733
references: Cell. 1997 Mar 7;88(5):717-23
references: 9054511
references: J Bacteriol. 2008 Jan;190(2):463-75
references: 17993515
references: J Bacteriol. 2003 Nov;185(22):6723-7
references: 14594849
references: Curr Opin Microbiol. 2007 Feb;10(1):17-23
references: 17208514
references: Proteins. 2009 Oct;77(1):235-41
references: 19544572
references: Mol Microbiol. 2008 May;68(3):786-99
references: 18373524
references: Cell. 2004 Nov 12;119(4):457-68
references: 15537536
references: J Mol Biol. 1998 Apr 24;278(1):219-29
references: 9571045
references: Nature. 1997 Dec 11;390(6660):580-6
references: 9403685
references: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19863-8
references: 19060201
references: Mol Microbiol. 1999 Nov;34(4):633-40
references: 10564504
references: Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2909-13
references: 7708747
references: Methods Mol Biol. 1995;47:253-9
references: 7550741
references: Mol Microbiol. 2009 Mar;71(6):1551-73
references: 19210621
references: Nat Rev Microbiol. 2009 Oct;7(10):724-35
references: 19756011
references: Med Vet Entomol. 2005 Dec;19(4):339-44
references: 16336297
references: J Bacteriol. 2009 Apr;191(8):2902-5
references: 19201806
references: Trends Biochem Sci. 2007 May;32(5):225-34
references: 17433693
references: Insect Mol Biol. 2002 Feb;11(1):79-86
references: 11841505
references: Science. 2010 Aug 13;329(5993):845-848
references: 20705859
references: J Bacteriol. 2009 Apr;191(8):2783-94
references: 19218390
references: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):670-5
references: 11209063
references: Cell Host Microbe. 2010 Oct 21;8(4):331-42
references: 20951967
references: J Med Entomol. 2003 May;40(3):364-70
references: 12943118
references: FEMS Microbiol Lett. 2001 Sep 11;203(1):11-21
references: 11557134
references: Insect Biochem Mol Biol. 2008 Jan;38(1):42-58
references: 18070664
references: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7247-52
references: 17438273
references: Mol Microbiol. 2011 Jul;81(1):219-31
references: 21542866
references: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3142-7
references: 14970347
references: J Insect Physiol. 2000 Jul 1;46(7):1069-1078
references: 10817833
references: Infect Immun. 2008 Sep;76(9):3844-53
references: 18573895
references: Front Biosci. 2008 May 01;13:7046-63
references: 18508715
references: FEBS Lett. 2010 Jun 18;584(12):2606-17
references: 20412802
references: Mol Microbiol. 2001 Feb;39(3):714-21
references: 11169111
references: J Biol Chem. 1999 Sep 3;274(36):25330-4
references: 10464258
references: Cell. 2008 Jun 13;133(6):1043-54
references: 18555780
references: J Clin Invest. 2009 Dec;119(12):3652-65
references: 19920352
references: AAPS PharmSci. 1999;1(2):E2
references: 11741199
references: Infect Immun. 2007 Mar;75(3):1517-9
references: 17158906
references: J Mol Biol. 2008 Jan 11;375(2):448-59
references: 18022195
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11001-6
references: 12949258
references: Mol Microbiol. 2006 Mar;59(5):1591-601
references: 16468997
references: PLoS Pathog. 2011 Jul;7(7):e1002102
references: 21750672
references: Exp Appl Acarol. 2002;28(1-4):135-40
references: 14570123
references: Microbiology (Reading). 2008 Sep;154(Pt 9):2641-2658
references: 18757798
references: PLoS Pathog. 2010 Sep 16;6(9):e1001104
references: 20862323
references: Nat Struct Mol Biol. 2009 Dec;16(12):1218-23
references: 19898477
references: Mol Microbiol. 2002 Jan;43(2):281-95
references: 11985709
references: Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7515-20
references: 20368453
references: Microbiol Mol Biol Rev. 2006 Dec;70(4):910-38
references: 17158704
references: Bioinformatics. 2006 Jan 15;22(2):195-201
references: 16301204
references: Exp Appl Acarol. 2002;28(1-4):127-34
references: 14570122
references: J Bacteriol. 2005 Nov;187(22):7845-52
references: 16267308
references: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17351-5
references: 20855615
references: Infect Immun. 2004 Dec;72(12):7147-54
references: 15557639
references: Infect Immun. 2009 Jul;77(7):2773-82
references: 19451251
references: Mol Microbiol. 2007 Sep;65(5):1193-217
references: 17645733
references: Infect Immun. 1997 Feb;65(2):412-21
references: 9009290
references: Front Biosci (Landmark Ed). 2009 Jan 01;14:2051-88
references: 19273185
references: J Clin Microbiol. 1993 May;31(5):1251-5
references: 8501226
references: J Bacteriol. 2005 Mar;187(5):1792-8
references: 15716451
references: Infect Immun. 2008 Dec;76(12):5694-705
references: 18809667
references: J Clin Invest. 1998 May 15;101(10):2240-50
references: 9593780
references: Annu Rev Microbiol. 2009;63:133-54
references: 19575571
references: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12724-9
references: 11675503
references: Curr Opin Microbiol. 2010 Apr;13(2):150-9
references: 20226724
references: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5162-7
references: 15743918
references: Nat Rev Microbiol. 2009 Apr;7(4):263-73
references: 19287449
references: Mol Microbiol. 2010 Jul 1;77(1):128-42
references: 20444101
references: Trends Biochem Sci. 2001 Jun;26(6):369-76
references: 11406410
references: Infect Immun. 2004 Nov;72(11):6433-45
references: 15501774
references: Annu Rev Entomol. 1995;40:245-67
references: 7810988
references: Microbiol Rev. 1993 Jun;57(2):320-46
references: 8336670
references: J Exp Med. 2004 Mar 1;199(5):641-8
references: 14981112
references: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references: 7984417
references: J Biochem. 1998 Aug;124(2):440-5
references: 9685739
references: PLoS Pathog. 2011 Jun;7(6):e1002133
references: 21738477
references: Annu Rev Genet. 2006;40:385-407
references: 16895465
references: J Clin Invest. 2004 Jan;113(2):220-30
references: 14722614
references: J Clin Microbiol. 2000 Jan;38(1):382-8
references: 10618120