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
Buonomo, Erica L; Petri Jr, William A (2016) The microbiota and immune response during Clostridium difficile infection. Anaerobe 41:79-84
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
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
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 16:432-43
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
Burgess, Stacey L; Petri Jr, William A (2016) The Intestinal Bacterial Microbiome and E. histolytica Infection. Curr Trop Med Rep 3:71-74
Naylor, Caitlin; Petri Jr, William A (2016) Leptin Regulation of Immune Responses. Trends Mol Med 22:88-98
Madan, Rajat; Petri Jr, William A (2015) Role of obesity and adipose tissue-derived cytokine leptin during Clostridium difficile infection. Anaerobe 34:182-6
Watanabe, Koji; Petri Jr, William A (2015) Molecular biology research to benefit patients with Entamoeba histolytica infection. Mol Microbiol 98:208-17
Verkerke, Hans P; Hanbury, Blake; Siddique, Abdullah et al. (2015) Multisite clinical evaluation of a rapid test for Entamoeba histolytica in stool. J Clin Microbiol 53:493-7

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