We will test if leptin receptor signaling in intestinal epithelial cells (IECs) protects from intestinal infection due to Entamoeba histolytica, both intrinsically within IECs by up-regulating repair pathways, and extrinsically by IEC-mediated recruitment of inflammatory cells to the intestine. Successful completion of these studies will identify the mechanism by which leptin receptor signaling acts in mucosal defense, with implications for the understanding of gut immune homeostasis. Significance: The importance of this project derives from the contribution of malnutrition to an estimated one-third of all deaths among children and 60% of deaths due to diarrhea, and to the contribution of amebiasis to severe diarrhea in children in the developing world. Innovative aspects of the proposal include that it challenges the existing paradigm that protein-energy malnutrition explains the infectious diseases susceptibility of malnourished children. In contrast this study identifies specific leptin mediated molecular pathways in intestinal epithelial cells that are altered in malnourished children and that contribute to infectious disease susceptibility The environment for the work includes active investigation of amebiasis in humans, murine models, and at the cellular level, and the Principal Investigator who has contributed to amebiasis research for over 25 years.

Public Health Relevance

Malnutrition contributes to an estimated one-third of all deaths among children and 60% of deaths due to diarrhea. This proposal will identify the mechanism by which lack of the nutritional hormone leptin increases susceptibility to amebiasis, with the potential of more broadly understanding why malnourished children suffer disproportionately from diarrhea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026649-25
Application #
8648949
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1989-08-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Burgess, Stacey L; Gilchrist, Carol A; Lynn, Tucker C et al. (2017) Parasitic Protozoa and Interactions with the Host Intestinal Microbiota. Infect Immun 85:
Gilmartin, Allissia A; Ralston, Katherine S; Petri Jr, William A (2017) Inhibition of Amebic Lysosomal Acidification Blocks Amebic Trogocytosis and Cell Killing. MBio 8:
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
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Shirley, Debbie-Ann; Moonah, Shannon (2016) Fulminant Amebic Colitis after Corticosteroid Therapy: A Systematic Review. PLoS Negl Trop Dis 10:e0004879
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
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Cowardin, Carrie A; Jackman, Brianna M; Noor, Zannatun et al. (2016) Glucosylation Drives the Innate Inflammatory Response to Clostridium difficile Toxin A. Infect Immun 84:2317-23
Buonomo, Erica L; Cowardin, Carrie A; Wilson, Madeline G et al. (2016) Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection. Cell Rep 16:432-443
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

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