Abstract

Mucosal and systemic immunity may be important for vaccines designed to prevent Trypanosoma cruzi and other mucosally invasive intracellular pathogens, but it is unknown whether optimal mucosal and systemic immunity can be induced concurrently. CD4+ Th1 cells (secreting IL-2, IFN-gamma and TNF-alpha) are important for systemic protection against intracellular pathogens. CD4+ Th2 cells (secreting IL-4, IL-5, IL-6 and IL-10) induce secretory IgA, protective against mucosal pathogens. However, reciprocal inhibitory actions between TH1 and Th2 cells exist. In addition, mucosal antigen delivery can induce immune tolerance associated with clonal deletion, anergy, or the induction of suppressor """"""""Th3"""""""" cells secreting high levels of TGF-Beta. It is of critical importance to the field of vaccine immunobiology to further define the interactions between mucosal and systemic immunity against mucosally invasive intracellular pathogens. We propose to investigate the relationships between mucosal and systemic T. cruzi immunity as a model system for studying these interactions. First, we will address the hypothesis that protective immunity induced by T. cruzi infection involves different molecular and cellular immune requirements in mucosal and systemic tissues. The importance of total B cells, IgA, class I and II restricted T cells, IFN-gamma, IL-4 and inducible nitric oxide synthase will be studied in BALB/c mice and mice with targeted disruptions in these immune functions. Second, we will study the hypothesis that vaccines inducing differential CD4+ Th1 and Th2 responses will have different effects on mucosal and systemic protection. Vaccines including T. cruzi antigens and cytokine adjuvants will be studied for protective effects against mucosal and systemic challenges. Third, we will study the hypothesis that recombinant BCG salmonella vaccines expressing T. cruzi antigens in both mucosal and systemic tissues can induce concurrent mucosal and systemic protection. Protective soluble protein and live recombinant vaccines will be studied in genetic knockout mice to identify the molecular and cellular requirements for immune protection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040196-04
Application #
6488978
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Hall, B Fenton
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$342,670
Indirect Cost

  Institution

Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103

  Publications

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

Showing the most recent 10 out of 11 publications