Immunologic Basis for Broad Protection against Enteric Fever Salmonella

伤寒沙门氏菌（Salmonella enterica serovar Typhi，S. Typhi）、伤寒沙门氏菌S.甲型副伤寒和甲型副伤寒副伤寒B是全球绝大多数肠热病的原因，是一个主要的公共卫生问题。此外，沙门氏菌属是B类病原体，有可能被用作生物恐怖武器。本申请的总体目标是通过鉴定可能在保护中起重要作用的体液和细胞介导的免疫应答（CMI）来促进针对肠热病的交叉保护疫苗的开发。第二个总体目标是提供数据来验证S。伤寒/沙门氏菌副伤寒：一种预防肠热病的二价疫苗。拟定研究将利用从口服Ty21a和CVD 909伤寒疫苗或减毒CVD 1902 S免疫的受试者中获得的外周血单核细胞和血清标本。甲型副伤寒候选疫苗，来自用野生型（wt）-S.伤寒和伤寒沙门氏菌。甲型副伤寒和伤寒、副伤寒流行区的甲型副伤寒患者。我们将利用先进的免疫学平台，如质量和传统的多色流式细胞术分析和分选的能力来表征S。伤寒沙门氏菌S.甲型和乙型副伤寒特异性B（[记忆]）（BM）、T [记忆]和T [调节]（T reg）反应，包括 它们的细胞因子产生和归巢/趋化因子受体表达的模式使用系统生物学类方法。我们还将进行免疫分析研究，以确定引起血清抗体反应的全基因组交叉反应蛋白。具体而言，我们建议测试以下假设： (1)一组定义的CMI响应在S之间的交叉保护中起关键作用。伤寒和沙门氏菌。伤寒沙门氏菌21a免疫受试者的乙型副伤寒感染;甲型副伤寒疫苗株（CVD 1902）或暴露于wt-S。甲型副伤寒对沙门氏菌有明确的CMI应答。甲型副伤寒抗原和与沙门氏菌交叉反应的感染细胞。伤寒和沙门氏菌。乙型副伤寒抗原;（3）口服免疫减毒沙门氏菌。甲型副伤寒CVD 1902疫苗或暴露于wt-S。甲型副伤寒（无论是在攻毒研究中还是在流行地区）可激发血清抗体和对沙门氏菌特异的BM、B效应细胞和Breguiatory细胞。甲型副伤寒，以及针对沙门氏菌常见抗原存在于S。伤寒和沙门氏菌。副伤寒B。这些研究将通过在人类中提供新的和独特的见解来促进该CETR应用的总体主题，这些见解有可能推进针对肠热病以及其他新兴肠道感染的疫苗策略的开发。

Infections with Salmonella enterica serovar Typhi (S. Typhi), S. Paratyphi A and S. Paratyphi B are responsible for the vast majority of enteric fevers globally and are a major public health concern. Additionally, Salmonella spp are category B pathogens that have the potential to be used as bio-terror weapons. The overall goal of this application is to advance the development of cross-protective vaccines against enteric fevers by identifying humoral and cell-mediated immune responses (CMI) which might play significant roles in protection. A secondary overall aim is to provide data to validate the S. Typhi /S. Paratyphi A bivalent vaccine approach to vaccination against enteric fevers. The proposed studies will take advantage of peripheral blood mononuclear cells and sera specimens obtained from subjects orally immunized with Ty21a and CVD 909 typhoid vaccines or with the attenuated CVD 1902 S. Paratyphi A candidate vaccine, from subjects challenged with wild-type (wt)-S. Typhi and wt-S. Paratyphi A and from typhoid and paratyphoid A patients in endemic areas. We will utilize the power of cutting edge immunologic platforms such as mass and conventional multichromatic flow cytometry analysis and sorting to characterize S. Typhi-, S. Paratyphi A-, and B-specific B([memory]) (BM), T [memory] �, and T [regulatory] (T reg) responses, including their patterns of cytokine production and homing/chemokine receptor expression using a systems biology like approach. We will also perform immunoprofiling studies to identify genome-wide cross-reactive proteins that elicit serum antibody responses. Specifically, we propose to test the following hypotheses: (1) a defined set of CMI responses play a key role in cross-protection between S. Typhi and S. Paratyphi B infection in Ty21a-immunized subjects, (2) oral immunization of volunteers with an attenuated S. Paratyphi A vaccine strain (CVD 1902) or exposed to wt-S. Paratyphi A elicits a defined set of CMI responses against S. Paratyphi A antigens and infected cells that cross-react with S. Typhi and S. Paratyphi B antigens, and (3) oral immunization with the attenuated S. Paratyphi A CVD 1902 vaccine or exposure to wt-S. Paratyphi A (either in challenge studies or in endemic areas) elicits serum antibodies and BM, Beffector, and Breguiatory cells specific to S. Paratyphi A, as well as against Salmonella common antigens present in S. Typhi and S. Paratyphi B. These studies will contribute to the overall theme of this CETR application by providing novel and unique insights in humans that have the potential to advance the development of vaccine strategies to enteric fevers as well as other emerging enteric infections.