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MEMORY IMMUNE MECHANISMS CONTRIBUTING TO PROTECTION AGAINST THE TISSUE-DWELLING NEMATODE PARASITE HELIGMOSOMOIDES POLYGYRUS

by
Timothy Kreider
M.D./Ph.D. Program

B.S. 2004, Massachusetts Institution of Technology

Thesis Advisor: William C. Gause, Ph.D.

Professor

Department of Medicine

MSB C-600

Tuesday, June 2, 2009
2:00 p.m.


Abstract

Gastrointestinal helminth infection is a significant global cause of morbidity. A model of intestinal nematode infection involves the murine parasite Heligmosomoides polygyrus. Oral inoculation of mice with H. polygyrus triggers a polarized Th2-type immune response associated with long-term chronic infection. However, drug cure followed by secondary challenge results in a faster, more effective host response that expels parasites within 2 weeks. The studies described herein examine the memory Th2-type response to H. polygyrus challenge, in particular the effects of an immune cell granuloma that forms at the host:parasite interface during the tissue-dwelling phase of H. polygyrus larva. The content and structure of this granuloma was characterized, and distinct populations including alternatively activated macrophages were identified. Effects of the early memory response to H. polygyrus larvae were observed including stunted development and impaired migration to the duodenum submucosa. Protective effects were also seen during the later lumen-dwelling phase with decreased viability and fecundity of adult parasites. Interference with macrophage function was investigated using inhibitors of arginase 1 and related enzymes associated with alternatively activated macrophages and previously implicated in the host response to helminthes. Inhibitors of arginase 1 and ornithine decarboxylase abrogated host clearance of secondary H. polygyrus inoculation, and administration of the ornithine decarboxylase product spermine was able to restore protection. Experiments with a conditional knockout mouse strain ArgFlox Tie2Cre, which lacks arginase 1 in macrophages, demonstrated intact immunity to H. polygyrus, but mice deficient in nitric oxide synthase 2, an enzyme that competes with arginase 1 for arginine metabolism in macrophages, had defective protection. This loss of protection manifested only late during the host response, suggesting an effect on the lumen-dwelling adult parasite. Both the early larval impairment and the later parasite clearance of an intact memory response were lost in B cell-deficient mice. Protection was recovered with transfer of serum from B cell-replete, H. polygyrus-challenged mice, signifying a crucial function for parasite-specific antibody. These studies suggest roles for antibodies and innate effector cells in mediating resistance against tissue-dwelling parasites and present novel assays for exploring these roles, important potential targets for the future development of vaccines and immunotherapies.


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