Title: The role of dendritic cells in T cell immunity to Cryptosporidium This application is for a Mentored Research Scientist Development Award (KO1) on Cryptosporidium, an enteric infection linked with serious human morbidity and mortality worldwide, and against which there is no effective therapy of prevention. Our goal is to elucidate the mechanisms by which immune cells initiate resistance against cryptosporidiosis with a view that a better understanding of the various components of the immune response will lead to development of effective vaccines and adjuvants to combat the infection in humans. Our central hypothesis is that DCs acquire parasite antigens when exposed to Cryptosporidium infection thereby priming specific T cell immunity. We base this on the observations that: 1) intestinal DCs located in the lamina propria directly sample pathogens by protruding dendrites into the gut lumen. DCs in Peyer's patch acquire intestinal antigens transferred by M cells;2) IL-12, which is produced predominantly by dendritic cells, is critical in inducing gamma interferon and controlling C. parvum infection;3) T cells, which can only be primed by dendritic cells, are indispensable in controlling the infection of Cryptosporidium. Based on these observations, the specific aims are designed to provide a comprehensive assessment of the nature of dendritic cell interaction with Cryptosporidium and induction of T cell immunity. They include: 1) Investigate Cryptosporidium antigen uptake by DCs following infection;2) Determine the mode of activation and migration of DCs after exposure to Cryptosporidium infection;3) Investigate dendritic cell-mediated T cell activation in response to Cryptosporidium infection. The proposed studies will provide the basis for understanding the mechanisms for the induction of T cell- mediated anti-Cryptosporidium immunity necessary for future design of vaccines and other methods of interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
3K01DK076549-03S2
Application #
7871977
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2007-04-01
Project End
2011-06-30
Budget Start
2009-07-25
Budget End
2011-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$54,000
Indirect Cost
Name
Tufts University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Perez-Cordon, Gregorio; Yang, Guilin; Zhou, Boping et al. (2014) Interaction of Cryptosporidium parvum with mouse dendritic cells leads to their activation and parasite transportation to mesenteric lymph nodes. Pathog Dis 70:17-27
Steele, Jennifer; Chen, Kevin; Sun, Xingmin et al. (2012) Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models. J Infect Dis 205:384-91
Wang, Haiying; Sun, Xingmin; Zhang, Yongrong et al. (2012) A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun 80:2678-88
Oezguen, Numan; Power, Trevor D; Urvil, Petri et al. (2012) Clostridial toxins: sensing a target in a hostile gut environment. Gut Microbes 3:35-41
Savidge, Tor C; Urvil, Petri; Oezguen, Numan et al. (2011) Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat Med 17:1136-41
Perez-Cordon, Gregorio; Nie, Weijia; Schmidt, Diane et al. (2011) Involvement of host calpain in the invasion of Cryptosporidium parvum. Microbes Infect 13:103-7
Sun, Xingmin; Wang, Haiying; Zhang, Yongrong et al. (2011) Mouse relapse model of Clostridium difficile infection. Infect Immun 79:2856-64
Zhang, Q; Feng, X; Nie, W et al. (2011) MyD88-dependent pathway is essential for the innate immunity to Enterocytozoon bieneusi. Parasite Immunol 33:217-25
Sun, Xingmin; Savidge, Tor; Feng, Hanping (2010) The enterotoxicity of Clostridium difficile toxins. Toxins (Basel) 2:1848-80
Steele, Jennifer; Feng, Hanping; Parry, Nicola et al. (2010) Piglet models of acute or chronic Clostridium difficile illness. J Infect Dis 201:428-34

Showing the most recent 10 out of 14 publications