Cryptosporidium parvum infections in immunocompromised individuals often develop into chronic, severe cryptosporidiosis that can become life-threatening. In conjunction with low CD4+ cell levels, other immune system factors are expected to contribute to infection chronicity in the immunodeficient host. 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 or 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. Consequently, a lack of response to these key antigens and development of certain cytokine profiles may lead to chronic, intractable infections. The overall goal of this proposal is to identify cryptosporidial antigens that are important in immune response and recovery. These antigens may be targets of antibody that block the attachment and penetration of invasive parasite stages, block fertilization in the sexual stages or may be targets of cell-mediated immune (CMI) responses. Recombinant antigens from a cDNA library, identified by their reactivity to specific anti-cryptosporidial antibodies and native antigen fractions will be used as the source of antigen. The applicants will establish the importance of each of these antigens by assessing their ability to elicit cellular immune responses using a mouse model. Since mucosal T-cells are thought to play a critical role in the immunity to this parasite, these antigens will also be evaluated for their ability to elicit in vitro responses from T-cells originating in the lamina propria and mesenteric lymph nodes as well as from IELs. The investigators will evaluate the various cytokines produced in response to these antigens in murine cell populations. Additionally, T-cell clones specific for 3-4 of these key antigens will be established and engrafted into infected mice. The ability of these cell lines will to reduce or clear infection will aid in determining if these antigens are important in response and in recovery. Successful use of prophylactic and treatment modalities requires an improved understanding of the natural immune mechanisms responsible for the control of the infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-4 (01))
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Wali, Tonu M
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Emory University
Schools of Medicine
United States
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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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