Philip R. Hardwidge
B.S. 1997, University of Illinois, Urbana
Ph.D. 2002, Mayo Clinic Graduate School
Fax: (785) 532-4851
Our laboratory is interested in understanding, treating, and preventing diarrheal disease caused by bacterial pathogens. We primarily 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.
We have discovered several molecular mechanisms by which bacterial proteins subvert the host innate immune system to promote bacterial colonization and transmission. We are employing our unique knowledge of these proteins and their mammalian targets to new studies of inflammatory diseases, metabolic syndrome, and cancer. We are also developing novel proteomic techniques to identify effective vaccine components and therapeutic targets in other bacterial pathogens.
Current NIH Funding
R01 AI099002 NIH/NIAID 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.
R21 AI092266 NIH/NIAID Reverse vaccinology of enterotoxigenic E. coli
The goal of this study is identify and characterize protective antigens for future development of ETEC vaccines.
R21 AI093913 NIH/NIAID Bacterial effector inhibition of type I interferon
The goal of this study is to determine how bacterial effectors inhibit type I interferon production.
R03 CA155868 NIH/NCI Delivery of a bacterial inhibitor of NF-kB to colon tumors
The goal of this study is to develop technologies to inhibit NF-kB activity in colon cancers.
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-kB 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. IKKb phosphorylates RPS3 to regulate its nuclear translocation and NF-kB 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 & Hardwidge PR. Enterotoxigenic Escherichia coli (ETEC) prevents host NF-kB activation by targeting IkBa 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-kB activation, Cell Host & Microbe, 2013, Jan;13(1):87-99. PMID: 23332158