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 #
5R01AI026649-24
Application #
8468611
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
1989-08-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
24
Fiscal Year
2013
Total Cost
$404,982
Indirect Cost
$147,022
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Burgess, Stacey L; Buonomo, Erica; Carey, Maureen et al. (2014) Bone marrow dendritic cells from mice with an altered microbiota provide interleukin 17A-dependent protection against Entamoeba histolytica colitis. MBio 5:e01817
Madan, Rajat; Guo, Xiaoti; Naylor, Caitlin et al. (2014) Role of leptin-mediated colonic inflammation in defense against Clostridium difficile colitis. Infect Immun 82:341-9
Cowardin, Carrie A; Petri Jr, William A (2014) Host recognition of Clostridium difficile and the innate immune response. Anaerobe 30:205-9
Linford, Alicia S; Jiang, Nona M; Edwards, Thomas E et al. (2014) Crystal structure and putative substrate identification for the Entamoeba histolytica low molecular weight tyrosine phosphatase. Mol Biochem Parasitol 193:33-44
Marie, Chelsea; Petri Jr, William A (2014) Regulation of virulence of Entamoeba histolytica. Annu Rev Microbiol 68:493-520
Ralston, Katherine S; Solga, Michael D; Mackey-Lawrence, Nicole M et al. (2014) Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion. Nature 508:526-30
Verkerke, Hans; Naylor, Caitlin; Zabeau, Lennart et al. (2014) Kinetics of leptin binding to the Q223R leptin receptor. PLoS One 9:e94843
Kato, Kentaro; Takegawa, Yasuhiro; Ralston, Katherine S et al. (2013) Sialic acid-dependent attachment of mucins from three mouse strains to Entamoeba histolytica. Biochem Biophys Res Commun 436:252-8
Mackey-Lawrence, Nicole M; Guo, Xiaoti; Sturdevant, Daniel E et al. (2013) Effect of the leptin receptor Q223R polymorphism on the host transcriptome following infection with Entamoeba histolytica. Infect Immun 81:1460-70
Moonah, Shannon N; Jiang, Nona M; Petri Jr, William A (2013) Host immune response to intestinal amebiasis. PLoS Pathog 9:e1003489

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