Cryptosporidium parvum infections in immunocompromised individuals often develop into chronic, severe cryptosporidiosis that can become life-threatening. In conjunction with low CD4+ cell levels, insufficiency of other immune system factors are expected to contribute to infection chronicity in the immunodeficient host. In contrast, cytokines such as gamma interferon (IFN-gamma) have been implicated in control of infection in both adults and children. Elucidation of immune responses and identification of features of immune dysregulation, such as cytokine abnormalities or inability of T-cells to proliferate in response to key cryptosporidial antigens, might identify patients at high risk for cryptosporidiosis. It is hypothesized that infection resolution in the immunocompetent host is linked to specific antigens responsible for the activation of lymphocyte populations and induction of cytokines and allows for protection from subsequent infections. Consequently, a lack of response to these key antigens and development of certain cytokine profiles may lead to chronic, intractable infections and limited, if any, protective responses. We have recently developed a model useful for evaluating protective immunity to C. parvum infection in adult experimental animals. This model, which uses IL-12 deficient or """"""""knockout"""""""" mice, is an important advance as previous tools were inadequate to effectively assess immunity. We now plan to use this model to determine the cell types and cytokines necessary for the generation and maintenance of protective immune responses. The necessity of subpopulation of lymphocytes will be determined by depletion of specific cell populations (e.g. CD4+, CD8+, and IEL cells) as well as key cytokines (IFN-gamma, IL-15 and IL-4) during primary and challenge infection of IL-12 knockout mice. To determine if protective responses identified by these experiments can be induced through immunization, immunodominant antigens (Cp40, Cp23, Cp17, Cp15, CpPO, CpP1, and CpP2) will be evaluated to determine if they can generate protective responses in our mouse vaccine model. This will be accomplished by immunizing mice with a DNA construct of these antigens, assessing their ability to elicit immune responses, and challenging mice with C. parvum to determine the degree of protection achieved.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036680-12
Application #
7585748
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
MO, Annie X Y
Project Start
1996-05-01
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2012-03-31
Support Year
12
Fiscal Year
2009
Total Cost
$210,146
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
McNair, Nina N; Mead, Jan R (2013) CD4? effector and memory cell populations protect against Cryptosporidium parvum infection. Microbes Infect 15:599-606
Bedi, B; Mead, J R (2012) Cryptosporidium parvum antigens induce mouse and human dendritic cells to generate Th1-enhancing cytokines. Parasite Immunol 34:473-85
Benitez, Alvaro; Priest, Jeffrey W; Ehigiator, Humphrey N et al. (2011) Evaluation of DNA encoding acidic ribosomal protein P2 of Cryptosporidium parvum as a potential vaccine candidate for cryptosporidiosis. Vaccine 29:9239-45
Mead, Jan R (2010) Challenges and prospects for a Cryptosporidium vaccine. Future Microbiol 5:335-7
Benitez, Alvaro J; McNair, Nina; Mead, Jan R (2009) Oral immunization with attenuated Salmonella enterica serovar Typhimurium encoding Cryptosporidium parvum Cp23 and Cp40 antigens induces a specific immune response in mice. Clin Vaccine Immunol 16:1272-8
Ehigiator, Humphrey N; Romagnoli, Pablo; Priest, Jeffrey W et al. (2007) Induction of murine immune responses by DNA encoding a 23-kDa antigen of Cryptosporidium parvum. Parasitol Res 101:943-50
Ehigiator, Humphrey N; McNair, Nina; Mead, Jan R (2007) Cryptosporidium parvum: the contribution of Th1-inducing pathways to the resolution of infection in mice. Exp Parasitol 115:107-13
Ehigiator, H N; Romagnoli, P; Borgelt, K et al. (2005) Mucosal cytokine and antigen-specific responses to Cryptosporidium parvum in IL-12p40 KO mice. Parasite Immunol 27:17-28
Smith, L M; Bonafonte, M T; Mead, J R (2000) Cytokine expression and specific lymphocyte proliferation in two strains of Cryptosporidium parvum-infected gamma-interferon knockout mice. J Parasitol 86:300-7
Bonafonte, M T; Smith, L M; Mead, J R (2000) A 23-kDa recombinant antigen of Cryptosporidium parvum induces a cellular immune response on in vitro stimulated spleen and mesenteric lymph node cells from infected mice. Exp Parasitol 96:32-41

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