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Related Research Units

Infectious Diseases Research

Research Overview

Our laboratory explores the interaction of commensal and pathogenic microbes with the host intestine using invertebrate and vertebrate model systems. We focus on regulation of bacterial metabolism and its impact on the host intestinal innate immune response and metabolic homeostasis. The following specific projects are ongoing in the laboratory:

  1. Conditional membrane association as a novel mechanism of bacterial transcription factor regulation.  We have identified two transcription factors that are regulated through reversible association with the bacterial inner membrane.  Transcription factor release from the membrane results from metabolically regulated post-transcriptional modification.  We are exploring the mechanism of membrane association, the impact of transcription factor membrane association on the bacterial transcriptome, and additional proteins that undergo reversible membrane association.
  2. Microbe-derived acetate control of histone acetylation in intestinal cells.  Using Drosophila as a model, we have identified a histone acetyltransferase expressed in intestinal cells that responds to acetate produced by intestinal bacteria.  This histone acetyltransferase co-regulates the intestinal innate immune response and lipid and glucose metabolism.  We are currently studying other intestinal functions regulated by this protein, the G-protein-coupled and innate immune receptors involved in the intestinal response to acetate, and biological sex-specific intestinal responses.  In addition, we are extending our observations to mammals using human enteroid-derived monolayers.
  3. Vibrio cholerae high cell density quorum sensing modulates the host intestinal innate immune response.  In both Drosophila and human enteroid models, we have discovered that bacterial quorum sensing modulates the intestinal innate immune response.  We are currently identifying the metabolites and bacterial structures responsible for this host response.

Research Background

Paula Watnick received her undergraduate degree in Chemistry from Princeton University.  She subsequently was awarded an ITT international fellowship to study multi-dimensional nuclear magnetic resonance techniques in the laboratory of Prof. Kurt Wuthrich at the Federal Institute of Technology in Zurich.  She returned to complete a PhD in Biophysical Chemistry with Dr. Sunney Chan at the California Institute of Technology and an MD at Yale Medical School.  She trained in Internal Medicine at Beth Israel Hospital, Boston and in Infectious Disease at the Massachusetts General Hospital. Her postdoctoral research was conducted in the laboratories of Dr. Stephen Calderwood at Massachusetts General Hospital and Dr. Roberto Kolter at Harvard Medical School.  Dr. Watnick is a fellow of the Infectious Diseases Society of America, the American Academy of Microbiology, and the American Association for the Advancement of Science.

 

Education

Graduate School

California Institute of Technology
1988 Pasadena CA

Medical School

Yale School of Medicine
1991 New Haven CT

Internship

Internal Medicine Beth Israel Deaconess Medical Center
1992 Boston MA

Residency

Internal Medicine Beth Israel Deaconess Medical Center
1993 Boston MA

Fellowship

Infectious Diseases Massachusetts General Hospital
1995 Boston MA

Publications

  1. Carbon source, cell density, and the microbial community control inhibition of V. cholerae surface colonization by environmental nitrate. bioRxiv. 2025 Jan 02. View Abstract
  2. Testosterone treatment impacts the intestinal microbiome of transgender individuals. mSphere. 2024 Oct 29; 9(10):e0055724. 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. Vibrio cholerae high cell density quorum sensing activates the host intestinal innate immune response. Cell Rep. 2022 09 20; 40(12):111368. View Abstract
  5. Bioengineered 3D Tissue Model of Intestine Epithelium with Oxygen Gradients to Sustain Human Gut Microbiome. Adv Healthc Mater. 2022 08; 11(16):e2200447. View Abstract
  6. The Short-Chain Fatty Acids Propionate and Butyrate Augment Adherent-Invasive Escherichia coli Virulence but Repress Inflammation in a Human Intestinal Enteroid Model of Infection. Microbiol Spectr. 2021 10 31; 9(2):e0136921. View Abstract
  7. Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex. Immunity. 2021 08 10; 54(8):1683-1697.e3. View Abstract
  8. The Interplay of Sex Steroids, the Immune Response, and the Intestinal Microbiota. Trends Microbiol. 2021 09; 29(9):849-859. View Abstract
  9. Methionine Availability in the Arthropod Intestine Is Elucidated through Identification of Vibrio cholerae Methionine Acquisition Systems. Appl Environ Microbiol. 2020 05 19; 86(11). View Abstract
  10. Vibrio cholerae Sheds Its Coat to Make Itself Comfortable in the Gut. Cell Host Microbe. 2020 02 12; 27(2):161-163. View Abstract
  11. Microbial Control of Intestinal Homeostasis via Enteroendocrine Cell Innate Immune Signaling. Trends Microbiol. 2020 02; 28(2):141-149. View Abstract
  12. A high-throughput, whole cell assay to identify compounds active against carbapenem-resistant Klebsiella pneumoniae. PLoS One. 2018; 13(12):e0209389. View Abstract
  13. Removal of a Membrane Anchor Reveals the Opposing Regulatory Functions of Vibrio cholerae Glucose-Specific Enzyme IIA in Biofilms and the Mammalian Intestine. mBio. 2018 09 04; 9(5). View Abstract
  14. A Self-Assembling Whole-Cell Vaccine Antigen Presentation Platform. J Bacteriol. 2018 08 01; 200(15). View Abstract
  15. The Drosophila Immune Deficiency Pathway Modulates Enteroendocrine Function and Host Metabolism. Cell Metab. 2018 09 04; 28(3):449-462.e5. View Abstract
  16. Sublingual Adjuvant Delivery by a Live Attenuated Vibrio cholerae-Based Antigen Presentation Platform. mSphere. 2018 06 27; 3(3). View Abstract
  17. Activation of Vibrio cholerae quorum sensing promotes survival of an arthropod host. Nat Microbiol. 2018 02; 3(2):243-252. View Abstract
  18. Vibrio cholerae ensures function of host proteins required for virulence through consumption of luminal methionine sulfoxide. PLoS Pathog. 2017 Jun; 13(6):e1006428. View Abstract
  19. Erysipelothrix rhusiopathiae Suppurative Arthritis in a 12-year-old Boy After an Unusual Fresh Water Exposure. Pediatr Infect Dis J. 2017 04; 36(4):431-433. View Abstract
  20. The interplay between intestinal bacteria and host metabolism in health and disease: lessons from Drosophila melanogaster. Dis Model Mech. 2016 Mar; 9(3):271-81. View Abstract
  21. Regulation of CsrB/C sRNA decay by EIIA(Glc) of the phosphoenolpyruvate: carbohydrate phosphotransferase system. Mol Microbiol. 2016 Feb; 99(4):627-39. View Abstract
  22. In situ proteolysis of the Vibrio cholerae matrix protein RbmA promotes biofilm recruitment. Proc Natl Acad Sci U S A. 2015 Aug 18; 112(33):10491-6. View Abstract
  23. The acetate switch of an intestinal pathogen disrupts host insulin signaling and lipid metabolism. Cell Host Microbe. 2014 Nov 12; 16(5):592-604. View Abstract
  24. The transcription factor Mlc promotes Vibrio cholerae biofilm formation through repression of phosphotransferase system components. J Bacteriol. 2014 Jul; 196(13):2423-30. View Abstract
  25. Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions. Cell Host Microbe. 2013 Sep 11; 14(3):294-305. View Abstract
  26. Mutations in the IMD pathway and mustard counter Vibrio cholerae suppression of intestinal stem cell division in Drosophila. mBio. 2013 Jun 18; 4(3):e00337-13. View Abstract
  27. Mannitol and the mannitol-specific enzyme IIB subunit activate Vibrio cholerae biofilm formation. Appl Environ Microbiol. 2013 Aug; 79(15):4675-83. View Abstract
  28. Glucose-specific enzyme IIA has unique binding partners in the vibrio cholerae biofilm. mBio. 2012 Nov 06; 3(6):e00228-12. View Abstract
  29. The bacterial biofilm matrix as a platform for protein delivery. mBio. 2012; 3(4):e00127-12. View Abstract
  30. The Drosophila protein mustard tailors the innate immune response activated by the immune deficiency pathway. J Immunol. 2012 Apr 15; 188(8):3993-4000. View Abstract
  31. A high-throughput screen identifies a new natural product with broad-spectrum antibacterial activity. PLoS One. 2012; 7(2):e31307. View Abstract
  32. Spatially selective colonization of the arthropod intestine through activation of Vibrio cholerae biofilm formation. Proc Natl Acad Sci U S A. 2011 Dec 06; 108(49):19737-42. View Abstract
  33. A communal bacterial adhesin anchors biofilm and bystander cells to surfaces. PLoS Pathog. 2011 Aug; 7(8):e1002210. View Abstract
  34. The phosphoenolpyruvate phosphotransferase system regulates Vibrio cholerae biofilm formation through multiple independent pathways. J Bacteriol. 2010 Jun; 192(12):3055-67. View Abstract
  35. Vibrio cholerae phosphoenolpyruvate phosphotransferase system control of carbohydrate transport, biofilm formation, and colonization of the germfree mouse intestine. Infect Immun. 2010 Apr; 78(4):1482-94. View Abstract
  36. Signals, regulatory networks, and materials that build and break bacterial biofilms. Microbiol Mol Biol Rev. 2009 Jun; 73(2):310-47. View Abstract
  37. Genetic analysis of Drosophila melanogaster susceptibility to intestinal Vibrio cholerae infection. Cell Microbiol. 2009 Mar; 11(3):461-74. View Abstract
  38. Genetic analysis of Vibrio cholerae monolayer formation reveals a key role for DeltaPsi in the transition to permanent attachment. J Bacteriol. 2008 Dec; 190(24):8185-96. View Abstract
  39. A novel role for enzyme I of the Vibrio cholerae phosphoenolpyruvate phosphotransferase system in regulation of growth in a biofilm. J Bacteriol. 2008 Jan; 190(1):311-20. View Abstract
  40. NspS, a predicted polyamine sensor, mediates activation of Vibrio cholerae biofilm formation by norspermidine. J Bacteriol. 2005 Nov; 187(21):7434-43. View Abstract
  41. Vibrio cholerae infection of Drosophila melanogaster mimics the human disease cholera. PLoS Pathog. 2005 Sep; 1(1):e8. View Abstract
  42. Identification of novel stage-specific genetic requirements through whole genome transcription profiling of Vibrio cholerae biofilm development. Mol Microbiol. 2005 Sep; 57(6):1623-35. View Abstract
  43. Role for glycine betaine transport in Vibrio cholerae osmoadaptation and biofilm formation within microbial communities. Appl Environ Microbiol. 2005 Jul; 71(7):3840-7. View Abstract
  44. Genetic evidence that the Vibrio cholerae monolayer is a distinct stage in biofilm development. Mol Microbiol. 2004 Apr; 52(2):573-87. View Abstract
  45. The Vibrio cholerae O139 O-antigen polysaccharide is essential for Ca2+-dependent biofilm development in sea water. Proc Natl Acad Sci U S A. 2003 Nov 25; 100(24):14357-62. View Abstract
  46. Role of ectoine in Vibrio cholerae osmoadaptation. Appl Environ Microbiol. 2003 Oct; 69(10):5919-27. View Abstract
  47. Environmental determinants of Vibrio cholerae biofilm development. Appl Environ Microbiol. 2003 Sep; 69(9):5079-88. View Abstract
  48. Identification and characterization of a Vibrio cholerae gene, mbaA, involved in maintenance of biofilm architecture. J Bacteriol. 2003 Feb; 185(4):1384-90. View Abstract
  49. Vibrio cholerae CytR is a repressor of biofilm development. Mol Microbiol. 2002 Jul; 45(2):471-83. View Abstract
  50. Paula I Watnick--elucidating the role of biofilms. Interview by Pam Das. Lancet Infect Dis. 2002 Mar; 2(3):190-2. View Abstract
  51. The absence of a flagellum leads to altered colony morphology, biofilm development and virulence in Vibrio cholerae O139. Mol Microbiol. 2001 Jan; 39(2):223-35. View Abstract
  52. Biofilm, city of microbes. J Bacteriol. 2000 May; 182(10):2675-9. View Abstract
  53. Vibrio cholerae VibF is required for vibriobactin synthesis and is a member of the family of nonribosomal peptide synthetases. J Bacteriol. 2000 Mar; 182(6):1731-8. View Abstract
  54. Steps in the development of a Vibrio cholerae El Tor biofilm. Mol Microbiol. 1999 Nov; 34(3):586-95. View Abstract
  55. A role for the mannose-sensitive hemagglutinin in biofilm formation by Vibrio cholerae El Tor. J Bacteriol. 1999 Jun; 181(11):3606-9. View Abstract
  56. Genetic approaches to study of biofilms. Methods Enzymol. 1999; 310:91-109. View Abstract
  57. The interaction of the Vibrio cholerae transcription factors, Fur and IrgB, with the overlapping promoters of two virulence genes, irgA and irgB. Gene. 1998 Mar 16; 209(1-2):65-70. View Abstract
  58. Purification of Vibrio cholerae fur and estimation of its intracellular abundance by antibody sandwich enzyme-linked immunosorbent assay. J Bacteriol. 1997 Jan; 179(1):243-7. View Abstract
  59. Hydrophobic mismatch in gramicidin A'/lecithin systems. Biochemistry. 1990 Jul 03; 29(26):6215-21. View Abstract
  60. Characterization of the transverse relaxation rates in lipid bilayers. Proc Natl Acad Sci U S A. 1990 Mar; 87(6):2082-6. View Abstract
  61. Conformations of model peptides in membrane-mimetic environments. Biophys J. 1982 Jan; 37(1):275-84. View Abstract

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