: Invasion of amoebae through the intestinal epithelium initiates amebic colitis, a disease estimated by the WHO to kill 100,000 people annualiy. We hypothesize that Entamoeba histolytica invasion requires intoxication of the epithelial cells lining the intestine by transfer of the 260 kDa lectin into the epithelial cell membrane. We propose that this is a 3 step process consisting of: (A) initial adherence to epithelial cell GaINAc via the GPI-linked 150 kDa parasite lectin; (B) secondary recruitment to the host-parasite interface of the integral membrane 260 kDa Ga1NAc lectin; and (C) insertion into the baso-lateral epithelial cell cytoplasm of the 260 kDa lectin cytoplasmic tail. Intoxication of the epithelial cells is hypothesized to result from the integrin motifs on the lectin cytoplasmic tail interfering with the binding of epithelial cell integrins to the extracellular matrix. We will test this through 4 specific aims.
Specific Aim 1 will complete the structural and functional characterization of the newly described 150 kDa lectin of E. histolytica.
Specific Aim 2 will study the interaction of the 150 kDa and 260 kDa lectins during amebic interaction with the epithelial cells.
Specific Aim 3 will test the mechanism and consequences of parasite transfer to epithelial cells of the 260 kDa lectin.
Specific Aim 4 will intervene in the adherence/invasion process by abrogating the functions of the 150 and/or 260 kDa lectins using RNA interference. SUCCESSFUL COMPLETION of these studies will unravel the enigma of amebic invasion and killing of humans, and promises to provide effective and rational approaches to the prevention and treatment of amebiasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026649-15
Application #
6631757
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1989-08-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
15
Fiscal Year
2003
Total Cost
$350,825
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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