Adherence of Entamoeba histolytica trophozoites to human colonic mucin glycoproteins, and contact-dependent killing of immune effector cells such as macrophages and neutrophils, require the activity of the galactose-specific adherence lectin. This amebic lectin also mediates resistance to serum lysis by interfering with the assembly of the membrane attack complex. The lectin is antigenically conserved in pathogenic zymodemes of E. histolytica, and is almost universally recognized by the humoral and cell mediated immune responses of individuals recovered from amebiasis. Immunization with the native lectin provides complete protection from the development of liver abscesses in 67% of immunized gerbils. Immunization of animals with the light subunit (expressed as an E. coli fusion protein) provides partial protection from amebic liver abscess. The lectin heterodimer has an apparently unprecedented mechanism of membrane anchorage: heavy subunit cDNA sequences predict it is transmembrane, while an acyl- glycosylphosphatidylinositol (GPI) anchor has been identified on the light subunit. Further study of the structure and function of the lectin is central to a molecular understanding of amebic pathogenesis. The goals of this proposal are to investigate the light subunit's role in adherence, cytolysis and serum resistance, and use monoclonal antibodies against pathogenic-specific epitopes on the lectin to develop new diagnostic tests for amebiasis.
Two specific aims are proposed: 1. to produce and use light subunit- specific antibodies to probe its contributions to the biologic activities ascribed to the lectin; and 2. to test the practical utility of anti- lectin antibodies to rapidly and specifically diagnose infection by pathogenic E. histolytica. It is proposed that an understanding of the molecular structure and function of the E. histolytica adherence lectin will not only provide fundamental insights toward the pathogenesis of amebiasis, but will yield a rapid diagnostic test for the disease and a basis for rational vaccine development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026649-10
Application #
2671925
Study Section
Special Emphasis Panel (ZRG5-BM-2 (03))
Project Start
1989-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Ghosh, Swagata; Leaton, Laura Ann; Farr, Laura et al. (2018) Interaction between parasite-encoded JAB1/CSN5 and macrophage migration inhibitory factor proteins attenuates its proinflammatory function. Sci Rep 8:10241
Burgess, Stacey L; Gilchrist, Carol A; Lynn, Tucker C et al. (2017) Parasitic Protozoa and Interactions with the Host Intestinal Microbiota. Infect Immun 85:
Ngobeni, Renay; Abhyankar, Mayuresh M; Jiang, Nona M et al. (2017) Entamoeba histolytica-Encoded Homolog of Macrophage Migration Inhibitory Factor Contributes to Mucosal Inflammation during Amebic Colitis. J Infect Dis 215:1294-1302
Gilmartin, Allissia A; Ralston, Katherine S; Petri Jr, William A (2017) Inhibition of Amebic Lysosomal Acidification Blocks Amebic Trogocytosis and Cell Killing. MBio 8:
Noor, Zannatun; Watanabe, Koji; Abhyankar, Mayuresh M et al. (2017) Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis. MBio 8:
Cowardin, Carrie A; Jackman, Brianna M; Noor, Zannatun et al. (2016) Glucosylation Drives the Innate Inflammatory Response to Clostridium difficile Toxin A. Infect Immun 84:2317-2323
Burgess, Stacey L; Saleh, Mahmoud; Cowardin, Carrie A et al. (2016) Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica. Infect Immun 84:2824-32
Shirley, Debbie-Ann; Moonah, Shannon (2016) Fulminant Amebic Colitis after Corticosteroid Therapy: A Systematic Review. PLoS Negl Trop Dis 10:e0004879
Cowardin, Carrie A; Buonomo, Erica L; Saleh, Mahmoud M et al. (2016) The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol 1:16108
Noor, Zannatun; Burgess, Stacey L; Watanabe, Koji et al. (2016) Interleukin-25 Mediated Induction of Angiogenin-4 Is Interleukin-13 Dependent. PLoS One 11:e0153572

Showing the most recent 10 out of 70 publications