This is an exploratory research grant that develops a novel therapeutic approach for treating African trypanosomiasis, a fatal human parasitic disease that has proven intractable to conventional immunotherapy. The present proposal examines the novel and exciting result that CpG oligodeoxynucleotide (ODN) treatment significantly enhances host resistance to trypanosomiasis. The biological effects include a marked increase in host survival, decreased parasite burden, enhanced innate and adaptive immunity, and alterations in parasite cellular differentiation. ? ? Therefore, the aims of this proposal are to elucidate the kinetics, breadth and the underlying mechanism of optimal CpG ODN therapy of experimental trypanosomiasis.
Specific Aim 1 examines CpG ODN-induced alterations in the infected host by measuring control of trypanosome tissue invasion, tissue-specific gene activation, innate immune cell stimulation, and parasite- specific B and T cell responses.
Specific Aim 2 tests the mechanistic hypothesis that amplification of the TLR9-, MyD88- and IRF7-dependent Type I IFN (IFN-1/2) pathway underlies CpG ODN enhancement of host resistance. An alternative hypothesis is also presented in which CpG ODN treatment amplifies innate immune system production of Type II IFN (IFN-3) which regulates trypanosome long-slender to short-stumpy cellular differentiation and host resistance. ? ? Overall, these novel and exciting studies provide a new therapeutic approach to controlling African trypanosomiasis that avoids many of the issues complicating current therapy of this disease.Project Narrative ? ? This exploratory project proposes an innovative approach to the control or cure of African trypanosomiasis, a fatal human parasitic disease. Successful completion of the aims will enable public health officers to treat trypanosome infected individuals with CpG oligodeoxynucleotides which will activate critical components of the innate immune system to control the disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI073346-01A1
Application #
7386897
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Wali, Tonu M
Project Start
2007-12-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
1
Fiscal Year
2008
Total Cost
$220,500
Indirect Cost
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Dagenais, Taylor R; Freeman, Bailey E; Demick, Karen P et al. (2009) Processing and presentation of variant surface glycoprotein molecules to T cells in African trypanosomiasis. J Immunol 183:3344-55
Dagenais, Taylor R; Demick, Karen P; Bangs, James D et al. (2009) T-cell responses to the trypanosome variant surface glycoprotein are not limited to hypervariable subregions. Infect Immun 77:141-51
Lopez, Rebecca; Demick, Karen P; Mansfield, John M et al. (2008) Type I IFNs play a role in early resistance, but subsequent susceptibility, to the African trypanosomes. J Immunol 181:4908-17
Mansfield, J M; Paulnock, D M (2008) Genetic manipulation of African trypanosomes as a tool to dissect the immunobiology of infection. Parasite Immunol 30:245-53