Immunologic Basis for Broad Protection against Enteric Fever Salmonella

沙门氏菌血清型伤寒、甲型副伤寒沙门氏菌和乙型副伤寒沙门氏菌感染是全球绝大多数肠道发热的原因，是一个主要的公共卫生问题。此外，沙门氏菌属B类病原体，有可能被用作生物恐怖武器。本应用的总体目标是通过识别可能在保护中发挥重要作用的体液和细胞介导的免疫反应（CMI）来推进针对肠热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伤寒沙门氏菌。副伤寒一种预防肠热的二价疫苗方法。拟议的研究将利用从口服Ty21a和CVD 909伤寒疫苗或CVD 1902 s副伤寒候选减毒疫苗或野生型(wt)-S攻毒的受试者中获得的外周血单个核细胞和血清标本。伤寒和wt-S。甲型副伤寒和来自伤寒和甲型副伤寒流行地区的病人。我们将利用尖端免疫平台的力量，如质量和传统的多色流式细胞术分析和分类，来表征伤寒沙门氏菌，副伤寒沙门氏菌A-和B-特异性B([记忆])(BM)， T[记忆]¿和T[调节]（T reg）反应，包括

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.