Live vector delivery systems can effectively target mucosal inductive sites for the efficacious delivery of vaccine antigens to induce both mucosal and systemic immunity. Typically, attenuated Salmonella vectors, adept at delivering vaccines to the Peyer's patches (PP) of the small intestine, elicit T helper (Th) 1 cell (IFN-g-dependent) immune responses to resolve this intracellular pathogen. However, our studies have shown that we can obtain elevated Th2 cell (IL-4-dependent) immune responses, followed by a delayed onset of Th1 cells, to colonization factor antigen I (CFA/I) from human enterotoxigenic Escherichia coli (ETEC) when expressed on the Salmonella cell surface (strain H696). Subsequent studies revealed that proinflammatory cytokine production and inflammatory cell infiltrates in the PP are attenuated. Such findings led us to question whether this is an anti-inflammatory vaccine. Consequently, mice orally immunized with Salmonella-CFA/l prevented proteolipidpeptide 139-151-mediated experimental autoimmune encephalitis (EAE) in an antigen-independent fashion as evidenced by reduced disease severity and complete recovery, in fact, minimal leukocyte infiltration into the central nervous system was observed. In contrast, S JL/J mice orally immunized with the Salmonella control strain or PBS showed progressive EAE and no recovery. Such evidence indicates that this vaccine functions systemically and nonspecifically by attenuating the innate and adaptive immune systems. To understand the mechanisms of action, we propose three Specific Aims. Studies in Specific Aim 1 will determine whether Salmonella-CFA/l suppresses or bypasses inflammation via induction of regulatory T cells or plasmacytoid dendritic cells. Studies in Specific Aim 2 will determine how Salmonella-CFA/l suppresses EAE, and whether this vaccine can be therapeutic for ongoing EAE. Studies also will determine whether protection can be adoptively transferred. Studies in Specific Aim 3 will determine whether expression of CFA/I fimbriae can redirect virulent Salmonella to alter its pathogenicity. Thus, from these studies we will learn the specific mechanisms induced by this anti-inflammatory vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041123-05
Application #
7013601
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
1999-01-01
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$276,350
Indirect Cost
Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Pascual, David W; Yang, Xinghong; Holderness, Kathryn et al. (2014) Regulatory T-cell vaccination independent of auto-antigen. Exp Mol Med 46:e82
Pascual, David W; Suo, Zhiyong; Cao, Ling et al. (2013) Attenuating gene expression (AGE) for vaccine development. Virulence 4:384-90
Yang, Xinghong; Suo, Zhiyong; Thornburg, Theresa et al. (2012) Expression of Escherichia coli virulence usher protein attenuates wild-type Salmonella. Virulence 3:29-42
Jun, Sangmu; Ochoa-Reparaz, Javier; Zlotkowska, Dagmara et al. (2012) Bystander-mediated stimulation of proteolipid protein-specific regulatory T (Treg) cells confers protection against experimental autoimmune encephalomyelitis (EAE) via TGF-ýý. J Neuroimmunol 245:39-47
Yang, Xinghong; Thornburg, Theresa; Holderness, Kathryn et al. (2011) Serum antibodies protect against intraperitoneal challenge with enterotoxigenic Escherichia coli. J Biomed Biotechnol 2011:632396
Suo, Zhiyong; Avci, Recep; Deliorman, Muhammedin et al. (2009) Bacteria survive multiple puncturings of their cell walls. Langmuir 25:4588-94
Suo, Zhiyong; Yang, Xinghong; Avci, Recep et al. (2009) Antibody selection for immobilizing living bacteria. Anal Chem 81:7571-8
Ochoa-Reparaz, Javier; Rynda, Agnieszka; Ascon, Miguel A et al. (2008) IL-13 production by regulatory T cells protects against experimental autoimmune encephalomyelitis independently of autoantigen. J Immunol 181:954-68
Kochetkova, Irina; Trunkle, Theresa; Callis, Gayle et al. (2008) Vaccination without autoantigen protects against collagen II-induced arthritis via immune deviation and regulatory T cells. J Immunol 181:2741-52
Suo, Zhiyong; Avci, Recep; Yang, Xinghong et al. (2008) Efficient immobilization and patterning of live bacterial cells. Langmuir 24:4161-7

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