IMMUNODOMINANT TARGETS OF CMI TO CRYPTOSPORIDIUM

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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.