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Infectious Diseases Research

Research Overview

Successful infection of a host organism by a bacterial pathogen depends critically on its ability to make the appropriate virulence factors at the right time and place. This is achieved through the coordinate regulation of virulence genes, the expression of which is typically controlled at the level of transcription by proteins that modulate the activity of RNA polymerase (RNAP). Research in my laboratory focuses on the regulation of transcription in pathogenic bacteria with emphasis on regulators that contact RNAP, and regulators that control virulence gene expression.

Several current projects concern the regulation of virulence gene expression in Pseudomonas aeruginosa, a pathogen that infects the lungs of cystic fibrosis (CF) patients. In the chronically infected CF lung the organism persists as a biofilm—a surface attached community of bacteria encased in a polymeric matrix. Prominent amongst those genes that play a role in biofilm formation in P. aeruginosa are the cupA genes, which encode components of a putative fimbrial structure that facilitates surface-attachment. We have found that MvaT, a member of the H-NS family of proteins, controls the phase-variable (i.e. ON/OFF) expression of the cupA fimbrial gene cluster. Current work is aimed at determining how MvaT exerts this control.

Other work in the laboratory involves the study of two related transcription regulators from the intracellular pathogen Francisella tularensis, the causative agent of tularemia. These two regulators form a complex that associates with RNAP to positively control virulence gene expression in this organism. We are interested in determining how these regulators, which do not appear to bind DNA, influence the expression of specific target genes.

We have begun to investigate the role that small 2-4 nucleotide RNA transcripts, “nanoRNAs” play in the regulation of gene expression in bacteria. We have shown that nanoRNAs can prime transcription initiation in vivo and that when they do this results in large and widespread changes in gene expression. These findings establish that small RNA primers can be used to initiate transcription in vivo, challenging the conventional view that all cellular transcription occurs using only NTPs. Our findings further suggest that nanoRNAs could represent a distinct class of functional small RNAs that can affect gene expression through direct incorporation into a target RNA transcript rather than through a traditional antisense-based mechanism.

Research Background

Simon Dove received his PhD from the University of Dundee in the UK and undertook Postdoctoral training in the Department of Microbiology and Molecular Genetics at Harvard Medical School.

Selected Publications

  1.  Goldman, S.R., Sharp, J.S., Vvedenskaya, I.O., Livny, J., Dove, S.L., and Nickels, B.E. (2011) NanoRNAs prime transcription initiation in vivo. Mol. Cell 42, 817-825.
  2. Castang, S., and Dove, S.L. (2010) High-order oligomerization is required for the function of the H-NS family member MvaT in Pseudomonas aeruginosa. Mol. Microbiol. 78, 916-931.
  3. Charity, J.C., Blalock, L.T., Costante-Hamm, M.M., Kasper, D.L., and Dove, S.L. (2009) Small molecule control of virulence gene expression in Francisella tularensis. PLoS Pathog. 5, e1000641.
  4. Turner, K.H., Vallet-Gely, I., and Dove, S.L. (2009) Epigenetic control of virulence gene expression in Pseudomonas aeruginosa by a LysR-type transcription regulator. PLoS Genet. 5, e1000779.

Publications

  1. Discovery of a glutathione utilization pathway in Francisella that shows functional divergence between environmental and pathogenic species. Cell Host Microbe. 2023 08 09; 31(8):1359-1370.e7. View Abstract
  2. Hfq-licensed RNA-RNA interactome in Pseudomonas aeruginosa reveals a keystone sRNA. Proc Natl Acad Sci U S A. 2023 05 23; 120(21):e2218407120. View Abstract
  3. Sequestration of a dual function DNA-binding protein by Vibrio cholerae CRP. Proc Natl Acad Sci U S A. 2022 Nov 16; 119(46):e2210115119. View Abstract
  4. Genome-wide protein-DNA interaction site mapping in bacteria using a double-stranded DNA-specific cytosine deaminase. Nat Microbiol. 2022 06; 7(6):844-855. View Abstract
  5. Novel anti-repression mechanism of H-NS proteins by a phage protein. Nucleic Acids Res. 2021 10 11; 49(18):10770-10784. View Abstract
  6. Identification of Group A Streptococcus Genes Directly Regulated by CsrRS and Novel Intermediate Regulators. mBio. 2021 08 31; 12(4):e0164221. View Abstract
  7. Improved transformation efficiency of group A Streptococcus by inactivation of a type I restriction modification system. PLoS One. 2021; 16(4):e0248201. View Abstract
  8. Control of a programmed cell death pathway in Pseudomonas aeruginosa by an antiterminator. Nat Commun. 2021 03 17; 12(1):1702. View Abstract
  9. H-NS-like proteins in Pseudomonas aeruginosa coordinately silence intragenic transcription. Mol Microbiol. 2021 06; 115(6):1138-1151. View Abstract
  10. Structural Basis for Virulence Activation of Francisella tularensis. Mol Cell. 2021 01 07; 81(1):139-152.e10. View Abstract
  11. Tn-Seq reveals hidden complexity in the utilization of host-derived glutathione in Francisella tularensis. PLoS Pathog. 2020 06; 16(6):e1008566. View Abstract
  12. Widespread targeting of nascent transcripts by RsmA in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2020 05 12; 117(19):10520-10529. View Abstract
  13. RNase E Promotes Expression of Type III Secretion System Genes in Pseudomonas aeruginosa. J Bacteriol. 2019 11 15; 201(22). View Abstract
  14. Loss of RNA Chaperone Hfq Unveils a Toxic Pathway in Pseudomonas aeruginosa. J Bacteriol. 2019 10 15; 201(20). View Abstract
  15. RocA Binds CsrS To Modulate CsrRS-Mediated Gene Regulation in Group A Streptococcus. mBio. 2019 07 16; 10(4). View Abstract
  16. Pervasive Targeting of Nascent Transcripts by Hfq. Cell Rep. 2018 05 01; 23(5):1543-1552. View Abstract
  17. Polyphosphate Kinase Antagonizes Virulence Gene Expression in Francisella tularensis. J Bacteriol. 2018 02 01; 200(3). View Abstract
  18. Dissection of the molecular circuitry controlling virulence in Francisella tularensis. Genes Dev. 2017 08 01; 31(15):1549-1560. View Abstract
  19. The Pneumococcal Type 1 Pilus Genes Are Thermoregulated and Are Repressed by a Member of the Snf2 Protein Family. J Bacteriol. 2017 08 01; 199(15). View Abstract
  20. Secreted Effectors Encoded within and outside of the Francisella Pathogenicity Island Promote Intramacrophage Growth. Cell Host Microbe. 2016 Nov 09; 20(5):573-583. View Abstract
  21. A response regulator promotes Francisella tularensis intramacrophage growth by repressing an anti-virulence factor. Mol Microbiol. 2016 08; 101(4):688-700. View Abstract
  22. s Factor and Anti-s Factor That Control Swarming Motility and Biofilm Formation in Pseudomonas aeruginosa. J Bacteriol. 2015 Nov 30; 198(5):755-65. View Abstract
  23. A Conserved Pattern of Primer-Dependent Transcription Initiation in Escherichia coli and Vibrio cholerae Revealed by 5' RNA-seq. PLoS Genet. 2015 Jul; 11(7):e1005348. View Abstract
  24. A self-lysis pathway that enhances the virulence of a pathogenic bacterium. Proc Natl Acad Sci U S A. 2015 Jul 07; 112(27):8433-8. View Abstract
  25. A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT. PLoS Pathog. 2015 Jun; 11(6):e1004967. View Abstract
  26. Ubiquitous promoter-localization of essential virulence regulators in Francisella tularensis. PLoS Pathog. 2015 Apr; 11(4):e1004793. View Abstract
  27. Single-molecule study on histone-like nucleoid-structuring protein (H-NS) paralogue in Pseudomonas aeruginosa: MvaU bears DNA organization mode similarities to MvaT. PLoS One. 2014; 9(11):e112246. View Abstract
  28. Coordinate control of virulence gene expression in Francisella tularensis involves direct interaction between key regulators. J Bacteriol. 2014 Oct; 196(19):3516-26. View Abstract
  29. Deep sequencing analyses expands the Pseudomonas aeruginosa AmpR regulon to include small RNA-mediated regulation of iron acquisition, heat shock and oxidative stress response. Nucleic Acids Res. 2014 Jan; 42(2):979-98. View Abstract
  30. Anr and its activation by PlcH activity in Pseudomonas aeruginosa host colonization and virulence. J Bacteriol. 2013 Jul; 195(13):3093-104. View Abstract
  31. Basis for the essentiality of H-NS family members in Pseudomonas aeruginosa. J Bacteriol. 2012 Sep; 194(18):5101-9. View Abstract
  32. Higher order oligomerization is required for H-NS family member MvaT to form gene-silencing nucleoprotein filament. Nucleic Acids Res. 2012 Oct; 40(18):8942-52. View Abstract
  33. Growth phase-dependent control of transcription start site selection and gene expression by nanoRNAs. Genes Dev. 2012 Jul 01; 26(13):1498-507. View Abstract
  34. Structural basis for type VI secretion effector recognition by a cognate immunity protein. PLoS Pathog. 2012; 8(4):e1002613. View Abstract
  35. An epigenetic switch mediates bistable expression of the type 1 pilus genes in Streptococcus pneumoniae. J Bacteriol. 2012 Mar; 194(5):1088-91. View Abstract
  36. The CgrA and CgrC proteins form a complex that positively regulates cupA fimbrial gene expression in Pseudomonas aeruginosa. J Bacteriol. 2011 Nov; 193(22):6152-61. View Abstract
  37. NanoRNAs prime transcription initiation in vivo. Mol Cell. 2011 Jun 24; 42(6):817-25. View Abstract
  38. NanoRNAs: a class of small RNAs that can prime transcription initiation in bacteria. J Mol Biol. 2011 Oct 07; 412(5):772-81. View Abstract
  39. Expression of the type 1 pneumococcal pilus is bistable and negatively regulated by the structural component RrgA. Infect Immun. 2011 Aug; 79(8):2974-83. View Abstract
  40. Nucleoid occlusion factor SlmA is a DNA-activated FtsZ polymerization antagonist. Proc Natl Acad Sci U S A. 2011 Mar 01; 108(9):3773-8. View Abstract
  41. A bacterial two-hybrid system that utilizes Gateway cloning for rapid screening of protein-protein interactions. Biotechniques. 2010 Nov; 49(5):831-3. View Abstract
  42. High-order oligomerization is required for the function of the H-NS family member MvaT in Pseudomonas aeruginosa. Mol Microbiol. 2010 Nov; 78(4):916-31. View Abstract
  43. Epigenetic control of virulence gene expression in Pseudomonas aeruginosa by a LysR-type transcription regulator. PLoS Genet. 2009 Dec; 5(12):e1000779. View Abstract
  44. Small molecule control of virulence gene expression in Francisella tularensis. PLoS Pathog. 2009 Oct; 5(10):e1000641. View Abstract
  45. The GacS/GacA signal transduction system of Pseudomonas aeruginosa acts exclusively through its control over the transcription of the RsmY and RsmZ regulatory small RNAs. Mol Microbiol. 2009 Aug; 73(3):434-45. View Abstract
  46. H-NS family members function coordinately in an opportunistic pathogen. Proc Natl Acad Sci U S A. 2008 Dec 02; 105(48):18947-52. View Abstract
  47. Rsd family proteins make simultaneous interactions with regions 2 and 4 of the primary sigma factor. Mol Microbiol. 2008 Dec; 70(5):1136-51. View Abstract
  48. Crystal structure and RNA binding of the Tex protein from Pseudomonas aeruginosa. J Mol Biol. 2008 Apr 11; 377(5):1460-73. View Abstract
  49. Local and global regulators linking anaerobiosis to cupA fimbrial gene expression in Pseudomonas aeruginosa. J Bacteriol. 2007 Dec; 189(23):8667-76. View Abstract
  50. Twin RNA polymerase-associated proteins control virulence gene expression in Francisella tularensis. PLoS Pathog. 2007 Jun; 3(6):e84. View Abstract
  51. Repression of phase-variable cup gene expression by H-NS-like proteins in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2005 Aug 02; 102(31):11082-7. View Abstract
  52. ExsE, a secreted regulator of type III secretion genes in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A. 2005 May 31; 102(22):8006-11. View Abstract
  53. An RNA polymerase mutant deficient in DNA melting facilitates study of activation mechanism: application to an artificial activator of transcription. J Mol Biol. 2004 Nov 05; 343(5):1171-82. View Abstract
  54. Characterization of presenilin-amyloid precursor interaction using bacterial expression and two-hybrid systems for human membrane proteins. Mol Membr Biol. 2004 Nov-Dec; 21(6):373-83. View Abstract
  55. A bacterial two-hybrid system based on transcription activation. Methods Mol Biol. 2004; 261:231-46. View Abstract
  56. RshA, an anti-sigma factor that regulates the activity of the mycobacterial stress response sigma factor SigH. Mol Microbiol. 2003 Nov; 50(3):949-59. View Abstract
  57. Region 4 of sigma as a target for transcription regulation. Mol Microbiol. 2003 May; 48(4):863-74. View Abstract
  58. Studying protein-protein interactions using a bacterial two-hybrid system. Methods Mol Biol. 2003; 205:251-65. View Abstract
  59. Protein-protein and protein-DNA interactions of sigma70 region 4 involved in transcription activation by lambdacI. J Mol Biol. 2002 Nov 15; 324(1):17-34. View Abstract
  60. Analysis of phosphorylation-dependent protein-protein interactions using a bacterial two-hybrid system. Sci STKE. 2002 Jul 23; 2002(142):pl11. View Abstract
  61. The bacteriophage T4 transcription activator MotA interacts with the far-C-terminal region of the sigma70 subunit of Escherichia coli RNA polymerase. J Bacteriol. 2002 Jul; 184(14):3957-64. View Abstract
  62. A role for interaction of the RNA polymerase flap domain with the sigma subunit in promoter recognition. Science. 2002 Feb 01; 295(5556):855-7. View Abstract
  63. Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists. Mol Pharmacol. 2001 Dec; 60(6):1210-25. View Abstract
  64. Bacterial two-hybrid analysis of interactions between region 4 of the sigma(70) subunit of RNA polymerase and the transcriptional regulators Rsd from Escherichia coli and AlgQ from Pseudomonas aeruginosa. J Bacteriol. 2001 Nov; 183(21):6413-21. View Abstract
  65. Magnitude of the CREB-dependent transcriptional response is determined by the strength of the interaction between the kinase-inducible domain of CREB and the KIX domain of CREB-binding protein. Mol Cell Biol. 2000 Dec; 20(24):9409-22. View Abstract
  66. Mechanism for a transcriptional activator that works at the isomerization step. Proc Natl Acad Sci U S A. 2000 Nov 21; 97(24):13215-20. View Abstract
  67. The outer membrane protein, antigen 43, mediates cell-to-cell interactions within Escherichia coli biofilms. Mol Microbiol. 2000 Jul; 37(2):424-32. View Abstract
  68. Isolation of peptide aptamers that inhibit intracellular processes. Proc Natl Acad Sci U S A. 2000 Feb 29; 97(5):2241-6. View Abstract
  69. Protein-protein contacts that activate and repress prokaryotic transcription. Cell. 1998 Mar 06; 92(5):597-600. View Abstract
  70. Conversion of the omega subunit of Escherichia coli RNA polymerase into a transcriptional activator or an activation target. Genes Dev. 1998 Mar 01; 12(5):745-54. View Abstract
  71. Use of artificial activators to define a role for protein-protein and protein-DNA contacts in transcriptional activation. Cold Spring Harb Symp Quant Biol. 1998; 63:173-80. View Abstract
  72. Activation of prokaryotic transcription through arbitrary protein-protein contacts. Nature. 1997 Apr 10; 386(6625):627-30. View Abstract
  73. Control of Escherichia coli type 1 fimbrial gene expression in stationary phase: a negative role for RpoS. Mol Gen Genet. 1997 Mar 18; 254(1):13-20. View Abstract
  74. Multicopy fimB gene expression in Escherichia coli: binding to inverted repeats in vivo, effect on fimA gene transcription and DNA inversion. Mol Microbiol. 1996 Sep; 21(6):1161-73. View Abstract
  75. The site-specific recombination system regulating expression of the type 1 fimbrial subunit gene of Escherichia coli is sensitive to changes in DNA supercoiling. Mol Microbiol. 1994 Dec; 14(5):975-88. View Abstract

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