Philip R. Hardwidge
B.S. Summa cum laude 1997, University of Illinois, Urbana, IL
Ph.D. 2002, Mayo Clinic Graduate School, Rochester, MN
Post-doctoral Fellow 2005, University of British Columbia, Vancouver, Canada
My laboratory is interested in understanding, treating, and preventing diarrheal disease caused by bacterial pathogens. We study several virotypes of Escherichia coli that cause diarrhea and malnutrition in humans and livestock, including E. coli O157:H7, non-O157 STEC, and enterotoxigenic E. coli (ETEC). These pathogens, as well as other enteric bacteria that use contact-dependent secretion systems, represent important threats to food safety, biosecurity, and animal health. In many cases, vaccines are not available or are ineffective, and the basic molecular microbiology of the host-pathogen interaction is relatively poorly understood. Additionally, bacterial virulence proteins utilize many molecular mechanisms that are also conserved among viruses of importance to biosecurity. My research team has discovered several mechanisms by which bacterial proteins subvert the host innate immune system to promote bacterial colonization and transmission. We are directing our knowledge of these proteins and their mammalian targets to innovative studies of metabolic syndromes, autoimmune disorders, and cancer. We are also developing proteomic techniques to identify vaccine targets in other organisms. I direct a dynamic and diverse team of postdoctoral fellows, Ph.D. students, technicians, and visiting research scholars to achieve these goals.
Current and Completed NIH Funding
NIH/NIAID AI127973 Functions of translocated bacterial glycosyltransferases
The goal of this study is to characterize a glycosyltransferase associated with bacterial virulence.
NIH/NIAID AI099002 Bacterial effectors targeting the IKK/NF-kB pathway
The goal of this study is to characterize E. coli virulence proteins that disrupt the host immune response.
NIH/NIAID AI101231 ETEC protein that antagonizes the NF-kB pathway
The goal of this study is to characterize how ETEC antagonizes pro-inflammatory signaling pathways.
NIH/NIAID AI092266 Reverse vaccinology of enterotoxigenic E. coli
The goal of this study was to identify protective antigens for future development of ETEC vaccines.
NIH/NIAID AI093913 Bacterial effector inhibition of type I interferon
The goal of this study was to determine how bacterial effectors inhibit type I interferon production.
NIH/NCI CA155868 Delivery of a bacterial inhibitor of NF-kB to colon tumors
The goal of this study was to develop technologies to inhibit NF-kB activity in colon cancers.
NIH/NIAID AI087686 Disruption of NF-kB signaling by diarrheagenic Escherichia coli
The goal of this study was to define the role of E. coli O157:H7 NleH proteins in disrupting NF-kB signaling.
NIH/NIAID AI087923 Bacterial effector subversion of host protein trafficking
The goal of this study was to define how bacterial pathogens exploit eukaryotic secretory pathways.
NIH/NIAID AI076227 Host subversion by E. coli O157:H7 effector proteins
The goal of this study was to identify E. coli virulence proteins that inhibit innate immunity.
NIH/NIAID AI070339 virulence factors in diarrheagenic E. coli pathogenesis
The goal of this study was to define the role of the NleF protein in enterohemorrhagic E. coli virulence.
Hardwidge PR,et al. Proteomic analysis of the intestinal epithelial cell response to enteropathogenic Escherichia coli. Journal of Biological Chemistry. 2004 May 7;279(19):20127-36. PMID: 14988394
Deng W, et al. Regulation of type III secretion hierarchy of translocators and effectors in attaching and effacing bacterial pathogens. Infection and Immunity. 2005 Apr;73(4):2135-46. PMC1087438 (see Faculty of 1000)
Hardwidge PR,et al. Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG. Infection and Immunity. 2005 May;73(5):2586-94. PMC1087329
Kim J, et al. The bacterial virulence factor NleA inhibits cellular protein secretion by disrupting mammalian COPII function. Cell Host and Microbe. 2007 Sep 13;2(3):160-71. PMID: 18005731 (see Faculty of 1000)
Gao X, et al. Bacterial effector binding to ribosomal protein S3 subverts NF-B function. PLoS Pathogens 2009. Dec;5(12):e1000708. PMC2791202
Johnson AM, et al. Heat-labile enterotoxin promotes Escherichia coli adherence to intestinal epithelial cells. Journal of Bacteriology. 2009 Jan;191(1):178-86. PMC2612432
Fleckenstein JM, et al. Molecular mechanisms of enterotoxigenic Escherichia coli infection, Microbes and Infection, 2010. Feb;12(2):89-98. PMID: 19883790
Shames SR, et al. The pathogenic E. coli type III effector EspZ interacts with host CD98 and facilitates host cell prosurvival signaling. Cellular Microbiology, 2010, Sep 1; 12(9):1322-39. PMID: 20374249
Wan F, et al. IKK phosphorylates RPS3 to regulate its nuclear translocation and NF-B specifier function, Nature Immunology 2011 Apr;12(4):335-43. PMID: 21399639 (see Faculty of 1000)
Wang X, et al. Heat-labile enterotoxin-induced activation of NF-kappaB and MAPK pathways in intestinal epithelial cells impacts enterotoxigenic Escherichia coli (ETEC) adherence, Cellular Microbiology, 2012 Aug;14(8):1231-41. PMID: 22452361
Pham T, et al. Functional differences and interactions between the E. coli type III secretion system effectors NleH1 and NleH2, Infection & Immunity, 2012 Jun;80(6):2133-40. PMID: 22451523
Wang X & HardwidgePR. Enterotoxigenic Escherichia coli (ETEC) prevents host NF-B activation by targeting IB polyubiquitination, Infection & Immunity, 2012, Dec;80(12):4417-25. PMID: 23027537
Gao X, et al. NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-B activation, Cell Host & Microbe, 2013, Jan;13(1):87-99. PMID: 23332158
Pham T, et al. Escherichia coli virulence protein NleH1 Interaction with
the v-crk Sarcoma Virus CT10 Oncogene-Like Protein (CRKL) Governs NleH1 Inhibition of the Ribosomal Protein S3 (RPS3)/NF-kappaB Pathway, Journal of Biological Chemistry, 2013, Nov 29;288(48):34567-74. PMID: 24145029
Rüter C & Hardwidge PR. “Drugs from Bugs”: Bacterial effector proteins as promising biological (immune-) therapeutics, FEMS Microbiology Letters, 2014, 351:126-132. PMID: 24261744
Feuerbacher LA & HardwidgePR. Influence of NleH effector expression, host genetics, and inflammation on Citrobacter rodentium colonization in mice, Microbes and Infection, 2014, May;16(5):429-33. PMID: 24613200
Kumar A, et al. Protective enterotoxigenic Escherichia coli antigens in a murine intranasal challenge model, PLoS Neglected Tropical Diseases, 2015, Aug 5;9(8):e0003924. PMID:26244636
Wang J, et al. Construction and sequencing of an infectious clone of the goose embryo-adapted Muscovy duck parvovirus vaccine strain FZ91-30, Virology Journal, 2016, Jun 21;13:104.PMID: 27329377
Gao X, et al.Citrobacter rodentium NleB Inhibits Tumor Necrosis Factor (TNF) Receptor-Associated Factor
3 (TRAF3) Ubiquitination to Reduce Host Type I Interferon Production, Journal of Biological Chemistry, 2016, Aug 26: 291(35):18232-8. PMID:27387501
Hays MP, et al.. Immunization with the MipA, Skp, or ETEC_2479 antigens confers protection against Enterotoxigenic E. coli strains expressing different colonization factors in a mouse pulmonary challenge model, Frontiers in Cellular and Infection Microbiology, 2016, Dec 12; 6:181. PMID:28018863
Ren W, et al. Intestinal Microbiota-Derived GABA Mediates Interleukin-17 Expression during Enterotoxigenic Escherichia coli Infection, Frontiers in Immunology, 2017, Jan 16;7:685. PMID:28138329
Gomarasca M, et al. Bacterial-derived cell-penetrating peptides deliver gentamicin to kill intracellular pathogens, Antimicrobial Agents and Chemotherapy, 2017, Jan 17. PMID:28096156