T. cruzi and other important human pathogens establish chronic infections after mucosal invasion, making both mucosal and systemic immune studies relevant for the development of protective vaccines. In our current RO1, we hypothesized that Th1 and Th2 cells would be differentially important for systemic and mucosal immunity, respectively, and mutually inhibitory. Contrary to our original hypotheses, we have shown that T. cruzi specific Th1 responses provide both optimal mucosal and systemic protection, strongly supporting the feasibility of vaccines designed to induce both optimal mucosal and systemic immunity concurrently. Further challenges remain, however. First, another important route of T. cruzi infection is through breaks in the skin. Safe and effective molecular vaccines capable of inducing mucosal, cutaneous and systemic T. cruzi protection must be developed. Second, although Th1 responses are more protective than Th2 responses, Th1 responses may not induce optimal secretory IgA also mechanistically important for mucosal protection. Third, the mechanisms involved in trafficking of vaccine-induced memory T cells to mucosal, cutaneous and systemic sites of T. cruzi infection are not known. We plan to further study T. cruzi as a model for investigations of the molecular and cellular relationships between mucosal, cutaneous and systemic immunity. We will study 3 major hypotheses: 1) Cruzipain and/or trans-sialidase specific immunity can protect against mucosal, cutaneous and systemic T. cruzi infection without inducing immunopathology, 2) Th1 biased vaccines induce serum IgG and secretory IgA responses protective against T. cruzi mucosal and cutaneous infection, and 3) Specific chemokine receptors and other trafficking molecules expressed on memory T cells are important for T. cruzi mucosal, cutaneous and systemic protection. Recombinant protein, DNA and live vaccines will be studied alone and in prime/boosting combinations. We will directly assess the protective effects of serum IgG, secretory IgA and B cells against mucosal and cutaneous challenges. Chemokine and/or integrin receptor expression will be studied by flow cytometry and RT-Real-Time PCR, and the in vivo effects of defective chemokine and integrin binding and/or signaling will be evaluated. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040196-06
Application #
6875221
Study Section
Special Emphasis Panel (ZRG1-VACC (04))
Program Officer
MO, Annie X Y
Project Start
1999-01-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$367,500
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Eickhoff, Christopher S; Zhang, Xiuli; Vasconcelos, Jose R et al. (2016) Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity. PLoS Pathog 12:e1005896
Sullivan, Nicole L; Eickhoff, Christopher S; Sagartz, John et al. (2015) Deficiency of antigen-specific B cells results in decreased Trypanosoma cruzi systemic but not mucosal immunity due to CD8 T cell exhaustion. J Immunol 194:1806-18
Eickhoff, Christopher Steven; Dunn, Brian Anthony; Sullivan, Nicole Lea et al. (2013) Comparison of the infectivity of Trypanosoma cruzi insect-derived metacyclic trypomastigotes after mucosal and cutaneous contaminative challenges. Mem Inst Oswaldo Cruz 108:508-11
Eickhoff, Christopher S; Schnapp, Anita R; Sagartz, John E et al. (2013) Lethal NK-mediated inflammation induced by IL-12 in the absence of polymorphic and nonpolymorphic MHC class I molecules. Cytokine 64:25-9
Sullivan, Nicole L; Eickhoff, Christopher S; Zhang, Xiuli et al. (2011) Importance of the CCR5-CCL5 axis for mucosal Trypanosoma cruzi protection and B cell activation. J Immunol 187:1358-68
Eickhoff, Christopher S; Vasconcelos, Jose R; Sullivan, Nicole L et al. (2011) Co-administration of a plasmid DNA encoding IL-15 improves long-term protection of a genetic vaccine against Trypanosoma cruzi. PLoS Negl Trop Dis 5:e983
Giddings, O K; Eickhoff, C S; Sullivan, N L et al. (2010) Intranasal vaccinations with the trans-sialidase antigen plus CpG Adjuvant induce mucosal immunity protective against conjunctival Trypanosoma cruzi challenges. Infect Immun 78:1333-8
Eickhoff, Christopher S; Giddings, Olivia K; Yoshida, Nobuko et al. (2010) Immune responses to gp82 provide protection against mucosal Trypanosoma cruzi infection. Mem Inst Oswaldo Cruz 105:687-91
Eickhoff, Christopher S; Lawrence, Cade T; Sagartz, John E et al. (2010) ECG detection of murine chagasic cardiomyopathy. J Parasitol 96:758-64
Hoft, Daniel F; Eickhoff, Christopher S; Giddings, Olivia K et al. (2007) Trans-sialidase recombinant protein mixed with CpG motif-containing oligodeoxynucleotide induces protective mucosal and systemic trypanosoma cruzi immunity involving CD8+ CTL and B cell-mediated cross-priming. J Immunol 179:6889-900

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