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100万人死亡的系统性疾病 死亡。考虑到这些感染对婴儿、老年人和免疫抑制的个人的影响， 安全有效的亚单位疫苗可能会对这种疾病产生巨大影响。虽然获得了显著的收益 已经在识别由系统免疫反应识别的沙门氏菌靶抗原方面取得了进展，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力至关重要。此应用程序将重点放在 保护性沙门氏菌活疫苗诱导的保护性组织驻留记忆Th1细胞及其鉴定 这些细胞识别的保护性靶标抗原。我们的实验方法是独特的，因为它将使用 自然水污染挑战，CD4 TRM Th1细胞积极参与的小鼠模型 保护性免疫，以及一套允许直接可视化沙门氏菌特异性CD4T细胞的工具。我们的 本申请特别提出：(I)确定组织驻留记忆T细胞在消除 持久性沙门氏菌，(Ii)发现独特的TRM T细胞受体，使其能够更好地预防 沙门氏菌感染，以及(Iii)识别该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效力。

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.