T. cruzi immune evasion factors and vaccine design

克氏锥虫免疫逃避因素和疫苗设计

• 批准号: 7448591
• 负责人: Karen A Norris
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448591
• 关键词: Acute; Address; Advanced Development; Affinity Chromatography; Animals; Antibody Formation; Antigen Targeting; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Blood; Cardiac; Cells; Chagas Disease; Chronic; Chronic Disease; Combined Vaccines; Complement; Complement Activation; DNA; Dose; Escherichia coli; Experimental Models; Failure; Generations; Goals; Hematogenous Spread; Histidine; Immune; Immune response; Immunization; Immunologics; In Vitro; Individual; Infection; Injection of therapeutic agent; Kinetics; Latin America; Lead; Location; Lymphocyte Activation; Lytic; Measures; Membrane Proteins; Memory; Metals; Mitogens; Modeling; Mus; Numbers; Outcome; Parasitemia; Parasites; Pathology; Plasma; Proliferating; Proline racemase; Proteins; Protocols documentation; Recombinants; Research; Risk; Staging; Stream; Survivors; System; T-Lymphocyte; Testing; Trypanosoma cruzi; Vaccinated; Vaccine Design; Vaccines; Virulence Factors; gastrointestinal; genetic regulatory protein; improved; in vivo; novel; pathogen; polyclonal B cell activator; prevent; response; vaccine development

DESCRIPTION (provided by applicant): As with other pathogens that establish chronic infections, immune evasion strategies of Trypanosoma cruzi likely contribute to the failure of the host to control and clear the infection. The identification and characterization of virulence factors involved in inducing immune dysregulation and evasion should lead to critical targets for the development of vaccines and improved chemotherapeutics. This study focuses on T. cruzi proline racemase (TcPRAC), which is secreted by vertebrate stage parasites and is a polyclonal B cell activator. This study will test the hypothesis that the immunization with sub- mitogenic doses of TcPRAC will result in neutralization of the mitogenic activity and improve early pathogen-specific responses to other vaccine candidates upon challenge. To test the hypothesis that neutralization of TcPRAC polyclonal activation leads to improved humoral response to other target antigens, the efficacy of a vaccine combination of TcPRAC and the T. cruzi complement regulatory protein (CRP) will be evaluated in a challenge model. The T. cruzi CRP is a surface protein involved in evasion of the alternative and classical complement activation, thus facilitating early hematogenous spread of the parasites. Other studies have shown CRP to be an effective vaccine candidate, however non-specific polyclonal responses to parasite challenge delay antigen- specific responses to the CRP and other vaccine candidates, thus limiting the capacity of these vaccines to prevent or ameliorate the establishment of chronic disease. To test the hypothesis that neutralization of a parasite-derived mitogen can improve the efficacy of host immune responses, the following Specific Aims will be addressed: 1) Characterization of the mitogenic capacity of recombinant TcPRAC in vivo, determination of sub-mitogenic doses and analyze B cell subsets and the location of the polyclonal response; 2) Analysis of the protective capacity of sub-mitogenic doses of TcPRAC in an in vivo T. cruzi challenge model; 3) Test the efficacy a TcPRAC and CRP vaccine combination. The novel attempt to alter the immune dysregulation induced by the T. cruzi mitogen by immunologic neutralization may enhance the efficacy of other vaccine candidates in this model and may offer a general approach to vaccine design for other pathogens that induce polyclonal responses. Relevance: The goals of this research is to advance development of a vaccine for Chagas' disease. Chagas' disease currently afflicts 20 million people in Latin America and another 90 million people are at risk of infection with Trypanosoma cruzi, the causative agent. No vaccine is currently available to prevent or treat Chagas' disease and the proposed studies will test two vaccine candidates in experimental models.

描述（由申请人提供）：与建立慢性感染的其他病原体一样，克鲁兹锥虫的免疫逃避策略可能导致宿主无法控制和清除感染。涉及诱导免疫失调和逃避的毒力因子的鉴定和表征应导致疫苗开发和改善化学疗法的关键靶标。这项研究的重点是克氏菌脯氨酸种族酶（TCPRAC），该植物由脊椎动物阶段寄生虫分泌，是多克隆B细胞活化剂。这项研究将检验以下假设：TCPRAC的下有丝原剂量的免疫将导致有丝分裂活性中和，并在挑战时改善对其他候选疫苗的早期病原体特异性反应。为了测试TCPRAC多克隆活化的中和导致对其他靶抗原的体液反应的改善，TCPRAC和Cruzi补体调节蛋白（CRP）的疫苗组合的疗效将在挑战模型中评估。 Cruzi CRP是一种参与逃避替代和经典补体激活的表面蛋白，从而促进了寄生虫的早期血源性传播。其他研究表明，CRP是一种有效的疫苗候选者，但是对寄生虫挑战的非特异性多克隆反应延迟了对CRP和其他疫苗候选者的特异性反应，因此限制了这些疫苗预防或改善慢性病的能力。为了检验寄生虫衍生的有丝分裂原的中和可以提高宿主免疫反应的功效的假设，将解决以下具体目标：1）体内重组TCPRAC的有丝分裂能力的表征，确定亚源剂量的确定和分析B细胞子群和分析B细胞子群以及该多隆隆响应的位置； 2）分析在体内Cruzi挑战模型中TCPRAC亚有效剂量的保护能力； 3）测试TCPRAC和CRP疫苗组合的功效。这种新的尝试改变了通过免疫学中和T. cruzi有丝分裂原质引起的免疫失调的尝试可以增强该模型中其他疫苗候选物的功效，并可能为诱导多克隆反应的其他病原体提供一种通用方法。相关性：这项研究的目标是推动开发摄影以用于查加斯疾病。目前，查加斯疾病在拉丁美洲遭受了2000万人的折磨，另外9000万人患有锥虫锥虫（Trypanosoma cruzi），这是病因剂。目前尚无疫苗来预防或治疗Chagas疾病，拟议的研究将在实验模型中测试两种疫苗候选物。