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. Our hypothesis is that immune responses affect the epithelial cell cytoskeleton through post-translational regulation of the adaptor protein ezrin. Ezrin links the plasma membrane to actin microfilaments and is essential for proper formation of microvilli. This proposal will test determine if immune responses against the parasite lead to changes in the function of ezrin in epithelial cells using mouse and in vitro models. The role of key signaling pathways and the ability to modulate these pathways with pharmacologicals will also be investigated.

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 malabsorption 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 giardiasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15AI094492-01
Application #
8101513
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$460,500
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
Barash, N R; Maloney, J G; Singer, S M et al. (2017) Giardia Alters Commensal Microbial Diversity throughout the Murine Gut. Infect Immun 85:
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
Keselman, Aleksander; Li, Erqiu; Maloney, Jenny et al. (2016) The Microbiota Contributes to CD8+ T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis. Infect Immun 84:2853-60
Solaymani-Mohammadi, Shahram; Lakhdari, Omar; Minev, Ivelina et al. (2016) Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules. J Leukoc Biol 99:475-82
Maloney, Jenny; Keselman, Aleksander; Li, Erqiu et al. (2015) Macrophages expressing arginase 1 and nitric oxide synthase 2 accumulate in the small intestine during Giardia lamblia infection. Microbes Infect 17:462-7
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
Bartelt, Luther A; Roche, James; Kolling, Glynis et al. (2013) Persistent G. lamblia impairs growth in a murine malnutrition model. J Clin Invest 123:2672-84
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
Kamda, Joel D; Nash, Theodore E; Singer, Steven M (2012) Giardia duodenalis: dendritic cell defects in IL-6 deficient mice contribute to susceptibility to intestinal infection. Exp Parasitol 130:288-91

Showing the most recent 10 out of 11 publications