The protozoan parasite Entamoeba histolytica causes amebiasis, which remains a major health problem in much of the world, and is considered a potential biological weapon. The two main forms of disease, amebic colitis and amebic liver abscess arise from complex interactions between the host and parasite. In the previous funding period, we focused primarily on the host, and established new paradigms about the role of inflammation and apoptosis in amebic disease. In this renewal we will return our focus to the parasite, and will look at what we have termed the amebic virulence program: E. histolytica molecules that must be expressed or suppressed to allow amebic invasion and survival within host tissues. We will define the virulence program through a transcriptional analysis, and ask how the virulence repertoire differs between amebic trophozoites in culture, those that have invaded into the colonic mucosa, and trophozoites within the liver. We will attempt to identify the requisite components of this response, and determine whether blocking their expression can alter the course of amebic colitis or amebic liver abscess. We will test the hypothesis that host macromolecules serve as triggers for the activation of the amebic virulence program, and test candidate amebic molecules for their role in recognizing host molecules and initiating the amebic virulence program: We will then determine whether blocking host macromolecule recognition, or signaling by amebic receptors, alters the course of amebic colitis. The above studies look at virulence in the context of amebic response to the host. We will also investigate the inherent virulence repertoire of E. histolytica HM1:IMSS by looking at differences at the transcriptional level between HM1:IMSS and the reduced virulence E. histolytica Rahman. When complete, these studies should provide new insights into the biology of E. histolytica, will further our understanding of the pathophysiology of amebic colitis and amebic liver abscess, and will identify new virulence factors that may play unique roles in amebic colitis or amebic liver abscess and could be targets for new vaccines or therapeutics. ERFORMANCE SITE(S) (organization,city,state) Washington University 660 South Euclid Avenue St. Louis, MO63110 PHS 398 (Rev. 09/04) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Stanley, Samuel L, Jr. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Samuel L. Stanley Jr. Stanleys Washington University Principal Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [X] No CH Yes If the proposed project Involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.gov/registrv/index.asp. Usecontinuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure Permission Statement Applicable to SBIR/STTR Only. See instructions, d Yes d No PHS 398 (Rev. 09/04) Page 3 Form Page 2-continued Number the followingpages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, First, Middle): Stanley, Samuel L. Jr. The name of the principal investigator/programdirector must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OFCONTENTS Page Numbers Face Page 1 Description,

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030084-18
Application #
7760850
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Wali, Tonu M
Project Start
1992-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
18
Fiscal Year
2010
Total Cost
$358,351
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Davis, Paul H; Chen, Minghe; Zhang, Xiaochun et al. (2009) Proteomic comparison of Entamoeba histolytica and Entamoeba dispar and the role of E. histolytica alcohol dehydrogenase 3 in virulence. PLoS Negl Trop Dis 3:e415
Sperandio, Brice; Regnault, Beatrice; Guo, Jianhua et al. (2008) Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med 205:1121-32
Snow, Margaret; Chen, Minghe; Guo, Jian et al. (2008) Differences in complement-mediated killing of Entamoeba histolytica between men and women--an explanation for the increased susceptibility of men to invasive amebiasis? Am J Trop Med Hyg 78:922-3
Melendez-Lopez, Samuel G; Herdman, Scott; Hirata, Ken et al. (2007) Use of recombinant Entamoeba histolytica cysteine proteinase 1 to identify a potent inhibitor of amebic invasion in a human colonic model. Eukaryot Cell 6:1130-6
Bullok, Kristin E; Maxwell, Dustin; Kesarwala, Aparna H et al. (2007) Biochemical and in vivo characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. Biochemistry 46:4055-65
Davis, Paul H; Schulze, Jochen; Stanley Jr, Samuel L (2007) Transcriptomic comparison of two Entamoeba histolytica strains with defined virulence phenotypes identifies new virulence factor candidates and key differences in the expression patterns of cysteine proteases, lectin light chains, and calmodulin. Mol Biochem Parasitol 151:118-28
Stanley Jr, S L (2006) Vaccines for amoebiasis: barriers and opportunities. Parasitology 133 Suppl:S81-6
Pelosof, Lorraine C; Davis, Paul H; Zhang, Zhi et al. (2006) Co-ordinate but disproportionate activation of apoptotic, regenerative and inflammatory pathways characterizes the liver response to acute amebic infection. Cell Microbiol 8:508-22
Davis, Paul H; Zhang, Xiaochun; Guo, Jianhua et al. (2006) Comparative proteomic analysis of two Entamoeba histolytica strains with different virulence phenotypes identifies peroxiredoxin as an important component of amoebic virulence. Mol Microbiol 61:1523-32
Snow, Margaret J; Stanley Jr, Samuel L (2006) Recent progress in vaccines for amebiasis. Arch Med Res 37:280-7

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