: 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.
|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:|
|Burgess, Stacey L; Petri Jr, William A (2016) The Intestinal Bacterial Microbiome and E. histolytica Infection. Curr Trop Med Rep 3:71-74|
|Buonomo, Erica L; Petri Jr, William A (2016) The microbiota and immune response during Clostridium difficile infection. Anaerobe 41:79-84|
|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|
Showing the most recent 10 out of 70 publications