肠道传染病每年在全球范围内造成超过10亿次疾病发作,导致大约200万人死亡。5岁以下的儿童和老人受到不成比例的影响。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)]等病原体,霍乱,志贺氏菌和大肠杆菌的多种致病型(E。大肠杆菌)。此外,多药耐药和广泛耐药(XDR)菌株(例如,伤寒链球菌H58菌株)的肠道细菌正在出现;因此,需要重新努力解决肠道疾病。这些肠道病原体中的许多可以通过口服或肠胃外疫苗来控制;然而,新的发展,有效的疫苗由于缺乏已知的免疫保护相关因素(CoP)和对导致保护性应答的因素的有限了解而受到阻碍。为了充分理解人类对肠道感染的反应,最近重新出现的一个非常有价值的工具是使用受控的人类感染模型(CHIMs),在该模型中,参与者受到毒性野生型(wt)生物的挑战.CHIMs有可能发现免疫机制并识别CoP对肠道病原体,以及评估治疗和疫苗在人类中的功效。CHIMs已被用于提供对发病机理的宝贵见解,宿主-病原体相互作用和疫苗评估。最近,已经进行了几项牛津伤寒CHIM研究,以评估多种细胞类型的作用(B细胞,CD8+T,Tregs,MAIT,伤寒沙门氏菌感染期间的单核细胞和DC)。从这些研究中出现的关键信息之一是基线抗原特异性反应是重要的,因为它们可以与临床结果相关。此外,发展为伤寒(TD)的志愿者表现出更高水平和更活化的细胞类型(例如,DC和单核细胞)在离散的信号传导途径中仍然有缺陷。这项研究的未来关键方面将涉及对进入部位肠道感染的免疫反应的研究,即,肠粘膜。这篇综述将描述我们目前对伤寒沙门氏菌和副伤寒沙门氏菌引起的肠热的免疫知识,强调CHIMs对揭示这些生物的复杂免疫反应的贡献,并提供对保护性免疫决定因素的见解。
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 by S. 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.