Target antigen identification to improve Salmonella vaccination

伤寒和非伤寒沙门氏菌病（NTS）是每年导致全球100万人死亡的全身性疾病。 死亡考虑到这些感染对婴儿、老年人和免疫抑制个体的影响， 安全有效的亚单位疫苗对这种疾病有巨大的影响。虽然取得了重大进展， 已经在确定沙门氏菌的靶抗原识别的全身免疫反应，我们 仍然对组织驻留淋巴细胞识别的靶抗原几乎一无所知， 我们现在知道这对沙门氏菌活疫苗的保护效果至关重要。该应用程序将集中于 保护性活沙门氏菌疫苗诱导的保护性组织驻留记忆（TRM）Th1细胞，并鉴定 这些细胞识别的保护性靶抗原。我们的实验方法是独一无二的， 自然水污染挑战，一种小鼠模型，其中CD4 TRM Th1细胞积极参与 保护性免疫，和一套工具，允许直接可视化沙门氏菌特异性CD4 T细胞。我们 本申请特别提出，（i）确定组织驻留记忆T细胞在消除免疫缺陷中的作用。 持久性沙门氏菌，（ii）发现独特的TRM T细胞受体，允许更大的保护， 沙门氏菌感染，和（iii）鉴定该T细胞亚群识别的抗原，并确定它们是否 可以提高沙门氏菌亚单位疫苗的有效性。

Typhoid and Non-Typhoidal Salmonellosis (NTS) are systemic diseases that annually cause 1 million global deaths. Given the impact of these infections on infants, the elderly, and immune suppressed individudals, a safe and effective sub-unit vaccine could have an enormous impact on this disease. While significant gains have been made in identifying the Salmonella target antigens recognized by systemic immune responses, we still know almost nothing about the target antigens recognized by tissue resident lymphocytes, a population that we now know is critical for the protective efficacy of live Salmonella vaccines. This application will focus on protective tissue resident memory (TRM) Th1 cells elicited by a protective live Salmonella vaccine and identify protective target antigens recognized by these cells. Our experimental approach is unique in that it will use natural water contamination challenge, a mouse model where CD4 TRM Th1 cells actively participate in protective immunity, and a set of tools that allow direct visualization of Salmonella-specific CD4 T cells. Our application specifically proposes to, (i) determine the role of tissue-resident memory T cells in the elimination of persistent Salmonella, (ii) uncover the unique TRM T cell receptors that allow greater protection against Salmonella infection, and (iii) identify the antigens recognized by this T cell subset and determine whether they can improve the effectiveness of a sub-unit vaccine for Salmonella.