Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G.
Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G.
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DOI：
10.1128/msphere.00988-19
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发表时间：
2020-09-23
期刊：
影响因子：
4.8
通讯作者：
Kaminski RW
中科院分区：
文献类型：
--
作者：
Clarkson KA;Frenck RW Jr;Dickey M;Suvarnapunya AE;Chandrasekaran L;Weerts HP;Heaney CD;McNeal M;Detizio K;Parker S;Hoeper A;Bourgeois AL;Porter CK;Venkatesan MM;Kaminski RW
志贺氏菌病免疫的相关因素尚未确定。由于先前的疾病以血清型特异性的方式防止随后的感染，调查感染前和感染后的免疫反应概况提供了一个机会，以确定可能与保护性免疫的发展和/或与攻击后发生志贺菌病风险降低相关的免疫标记物。这项研究首次报道了sonnei 53G攻击后免疫反应的广泛特征。结果表明，志贺氏菌病的进展与肠道炎症和粘膜肠道归巢反应密切相关。本研究的一个重要发现是志贺氏菌lps特异性血清IgA和记忆性B细胞IgA反应在基线时升高与疾病风险降低相关。基线IgA反应的增加可能导致本研究中观察到的剂量反应缺乏，这表明IgA反应作为免疫的潜在相关因素应进一步研究。志贺氏菌是造成中度至重度腹泻的主要原因，主要影响生活在低收入和中等收入国家的儿童（5岁以下）。几种候选疫苗正在开发中，控制人类感染模型（CHIMs）可成为提供疫苗效力早期评估和可能支持许可的有用工具。制作并评估了sonnei 53G冻干菌株，以确定安全且可重复地诱导≥60%发作率的剂量。在攻击前后收集样本，以评估肠道炎症反应、抗原特异性血清和粘膜抗体反应、功能性抗体反应和记忆B细胞反应。sonnei 53G感染引起了强烈的肠道炎症反应，血清和粘膜分泌物中存在抗原特异性抗体，α4β7肠道归巢标记阳性的抗原特异性IgA和igg分泌B细胞。临床疾病结局与攻击后的全身或功能性抗体反应之间没有关联；然而，更高的脂多糖（LPS）特异性血清IgA和IgA分泌记忆B细胞反应与攻击后疾病风险降低相关。本研究对sonnei 53G感染前后的免疫反应提供了独特的见解，有助于指导未来疫苗的合理设计，以诱导更类似于感染引发的保护性免疫反应。重要性：志贺氏菌病的免疫相关性尚未确定。由于先前的疾病以血清型特异性的方式防止随后的感染，调查感染前和感染后的免疫反应概况提供了一个机会，以确定可能与保护性免疫的发展和/或与攻击后发生志贺菌病风险降低相关的免疫标记物。这项研究首次报道了sonnei 53G攻击后免疫反应的广泛特征。结果表明，志贺氏菌病的进展与肠道炎症和粘膜肠道归巢反应密切相关。本研究的一个重要发现是志贺氏菌lps特异性血清IgA和记忆性B细胞IgA反应在基线时升高与疾病风险降低相关。基线IgA反应的增加可能导致本研究中观察到的剂量反应缺乏，这表明IgA反应作为免疫的潜在相关因素应进一步研究。
Correlate(s) of immunity have yet to be defined for shigellosis. As previous disease protects against subsequent infection in a serotype-specific manner, investigating immune response profiles pre- and postinfection provides an opportunity to identify immune markers potentially associated with the development of protective immunity and/or with a reduced risk of developing shigellosis postchallenge. This study is the first to report such an extensive characterization of the immune response after challenge with S. sonnei 53G. Results demonstrate an association of progression to shigellosis with robust intestinal inflammatory and mucosal gut-homing responses. An important finding in this study was the association of elevated Shigella LPS-specific serum IgA and memory B cell IgA responses at baseline with reduced risk of disease. The increased baseline IgA responses may contribute to the lack of dose response observed in the study and suggests that IgA responses should be further investigated as potential correlates of immunity. Shigella is a major cause of moderate to severe diarrhea largely affecting children (<5 years old) living in low- and middle-income countries. Several vaccine candidates are in development, and controlled human infection models (CHIMs) can be useful tools to provide an early assessment of vaccine efficacy and potentially support licensure. A lyophilized strain of S. sonnei 53G was manufactured and evaluated to establish a dose that safely and reproducibly induced a ≥60% attack rate. Samples were collected pre- and postchallenge to assess intestinal inflammatory responses, antigen-specific serum and mucosal antibody responses, functional antibody responses, and memory B cell responses. Infection with S. sonnei 53G induced a robust intestinal inflammatory response as well as antigen-specific antibodies in serum and mucosal secretions and antigen-specific IgA- and IgG-secreting B cells positive for the α4β7 gut-homing marker. There was no association between clinical disease outcomes and systemic or functional antibody responses postchallenge; however, higher lipopolysaccharide (LPS)-specific serum IgA- and IgA-secreting memory B cell responses were associated with a reduced risk of disease postchallenge. This study provides unique insights into the immune responses pre- and postinfection with S. sonnei 53G in a CHIM, which could help guide the rational design of future vaccines to induce protective immune responses more analogous to those triggered by infection. IMPORTANCE Correlate(s) of immunity have yet to be defined for shigellosis. As previous disease protects against subsequent infection in a serotype-specific manner, investigating immune response profiles pre- and postinfection provides an opportunity to identify immune markers potentially associated with the development of protective immunity and/or with a reduced risk of developing shigellosis postchallenge. This study is the first to report such an extensive characterization of the immune response after challenge with S. sonnei 53G. Results demonstrate an association of progression to shigellosis with robust intestinal inflammatory and mucosal gut-homing responses. An important finding in this study was the association of elevated Shigella LPS-specific serum IgA and memory B cell IgA responses at baseline with reduced risk of disease. The increased baseline IgA responses may contribute to the lack of dose response observed in the study and suggests that IgA responses should be further investigated as potential correlates of immunity.