Giardia lamblia is the most common protozoan cause of diarrhea in the world. It infects ~500 million people worldwide resulting in nutrient malabsorption which can lead to cognitive developmental defects in children. Mechanisms of pathogenesis in giardiasis are poorly understood, hindering efforts to both treat and prevent this disease. Data suggest that immune responses contribute to pathology by inducing shortening of the microvilli on intestinal epithelial cells that provide an enhanced surface area for nutrient absorption. Other studies indicate that changes occur in the tight junctions between epithelial cells resulting in increased epithelial permeability further hindering proper absorption of nutrients. This proposal will examine a novel hypothesis, that immune responses induce expression of a microRNA which reduces expression of key elements of the microvilli, resulting in both the reduction of microvillous surface area and increases in epithelial permeability. The role of immune responses in inducing production of this microRNA will be tested using genetically immunodeficient mice as well as by adoptively transferring select immune cells from infected mice to naive individuals. The role of the microRNA in pathogenesis will also be tested in vivo using mice which lack the gene encoding this microRNA and in vitro by overexpressing this transcript in intestinal epithelial cell cultures. Expression of microRNA targets, epithelial permeability and nutrient absorption will be analyzed both in vivo and in vitro.

Public Health Relevance

Giardia is the most common protozoan cause of diarrhea in the US and is also considered a Biodefense Category B threat agent. The studies in this proposal will improve public health by examining how this infection causes nutrient malabsortion that can lead to defects in cognitive development. This information will provide new strategies for treating common diseases like celiac disease and inflammatory bowel disease as well as diarrheal diseases like Giardia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI081033-02
Application #
7748990
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2008-12-15
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$75,983
Indirect Cost
Name
Georgetown University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Li, Erqiu; Tako, Ernest A; Singer, Steven M (2016) Complement Activation by Giardia duodenalis Parasites through the Lectin Pathway Contributes to Mast Cell Responses and Parasite Control. Infect Immun 84:1092-9
Li, Erqiu; Liu, Mingqiu; Singer, Steven M (2014) Resistance to reinfection in mice as a vaccine model for giardiasis. Hum Vaccin Immunother 10:1536-43
Tako, Ernest A; Hassimi, Maryam F; Li, Erqiu et al. (2013) Transcriptomic analysis of the host response to Giardia duodenalis infection reveals redundant mechanisms for parasite control. MBio 4:e00660-13
Solaymani-Mohammadi, S; Singer, S M (2013) Regulation of intestinal epithelial cell cytoskeletal remodeling by cellular immunity following gut infection. Mucosal Immunol 6:369-78
Solaymani-Mohammadi, Shahram; Singer, Steven M (2011) Host immunity and pathogen strain contribute to intestinal disaccharidase impairment following gut infection. J Immunol 187:3769-75
Solaymani-Mohammadi, Shahram; Genkinger, Jeanine M; Loffredo, Christopher A et al. (2010) A meta-analysis of the effectiveness of albendazole compared with metronidazole as treatments for infections with Giardia duodenalis. PLoS Negl Trop Dis 4:e682
Solaymani-Mohammadi, Shahram; Singer, Steven M (2010) Giardia duodenalis: the double-edged sword of immune responses in giardiasis. Exp Parasitol 126:292-7