Controlled human infectious models, a path forward in uncovering immunological correlates of protection: Lessons from enteric fevers studies.
Controlled human infectious models, a path forward in uncovering immunological correlates of protection: Lessons from enteric fevers studies.
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DOI：
10.3389/fmicb.2022.983403
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
肠道传染病每年在全世界造成10多亿起疾病发作，导致约200万人死亡，其中5岁以下儿童和老年人受到的影响不成比例。肠道病原体包括病毒、寄生虫和细菌；后者包括沙门氏菌[伤寒(TS)和非伤寒(NTS)]、霍乱、志贺氏菌和多种类型的大肠杆菌(E.coli)等病原体。此外，肠道细菌的多重耐药和广泛耐药(XDR)菌株(例如伤寒沙门氏菌H58菌株)正在出现；因此，需要重新努力应对肠道疾病。这些肠道病原体中的许多可以通过口服或非肠道疫苗来控制；然而，由于缺乏已知的免疫学保护相关性(COP)和对影响保护性反应的因素的有限了解，新的有效疫苗的开发一直受到阻碍。为了完全理解人类对肠道感染的反应，最近重新出现的一个宝贵工具是使用受控人类感染模型(CHIM)，在该模型中，参与者被毒力较强的野生型(Wt)微生物挑战。CHIM有可能揭示免疫机制，识别COP对肠道病原体的抵抗力，以及评估疗法和疫苗在人类中的疗效。CHIM已被用于在疫苗的发病机制、宿主-病原体相互作用和评估方面提供宝贵的见解。最近，几项牛津伤寒Chim研究已经评估了多种细胞类型(B细胞、CD8+T、Tregs、MAIT、单核细胞和DC)在伤寒沙门氏菌感染中的作用。从这些研究中得出的一个关键信息是，基线抗原特异性反应很重要，因为它们可以与临床结果相关。此外，患有伤寒(TD)的志愿者表现出更高的水平和更多激活的细胞类型(例如DC和单核细胞)，但这些细胞在离散的信号通路中仍存在缺陷。这项研究未来的关键方面将涉及对进入部位即肠道粘膜对肠道感染的免疫反应的研究。这篇综述将描述我们目前对由YS引起的肠热的免疫力的了解。伤寒和甲型副伤寒沙门氏菌，重点是CHIM在揭示对这些生物的复杂免疫反应方面的贡献，并为保护性免疫的决定因素提供见解。
Enteric infectious diseases account for more than a billion disease episodes yearly worldwide resulting in approximately 2 million deaths, with children under 5 years old and the elderly being disproportionally affected. Enteric pathogens comprise viruses, parasites, and bacteria; the latter including pathogens such as Salmonella [typhoidal (TS) and non-typhoidal (nTS)], cholera, Shigella and multiple pathotypes of Escherichia coli (E. coli). In addition, multi-drug resistant and extensively drug-resistant (XDR) strains (e.g., S. Typhi H58 strain) of enteric bacteria are emerging; thus, renewed efforts to tackle enteric diseases are required. Many of these entero-pathogens could be controlled by oral or parenteral vaccines; however, development of new, effective vaccines has been hampered by lack of known immunological correlates of protection (CoP) and limited knowledge of the factors contributing to protective responses. To fully comprehend the human response to enteric infections, an invaluable tool that has recently re-emerged is the use of controlled human infection models (CHIMs) in which participants are challenged with virulent wild-type (wt) organisms. CHIMs have the potential to uncover immune mechanisms and identify CoP to enteric pathogens, as well as to evaluate the efficacy of therapeutics and vaccines in humans. CHIMs have been used to provide invaluable insights in the pathogenesis, host-pathogen interaction and evaluation of vaccines. Recently, several Oxford typhoid CHIM studies have been performed to assess the role of multiple cell types (B cells, CD8+ T, Tregs, MAIT, Monocytes and DC) during S. Typhi infection. One of the key messages that emerged from these studies is that baseline antigen-specific responses are important in that they can correlate with clinical outcomes. Additionally, volunteers who develop typhoid disease (TD) exhibit higher levels and more activated cell types (e.g., DC and monocytes) which are nevertheless defective in discrete signaling pathways. Future critical aspects of this research will involve the study of immune responses to enteric infections at the site of entry, i.e., the intestinal mucosa. This review will describe our current knowledge of immunity to enteric fevers caused byS. Typhi and S. Paratyphi A, with emphasis on the contributions of CHIMs to uncover the complex immunological responses to these organisms and provide insights into the determinants of protective immunity.
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