Determinants of immune responses predictive of protection against shigellosis in an endemic zone: a systems analysis of antibody profiles and function

IF 20.9 1区 生物学 Q1 INFECTIOUS DISEASES Lancet Microbe Pub Date : 2024-10-01 DOI:10.1016/S2666-5247(24)00112-5
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引用次数: 0

Abstract

Background

Shigella is the third leading global cause of moderate or severe diarrhoea among children younger than 5 years globally, and is the leading cause in children aged 24–59 months. The mechanism of protection against Shigella infection and disease in endemic areas is uncertain. We aimed to compare the Shigella-specific antibody responses in individuals living in Shigella-endemic and non-endemic areas, and to identify correlates of protection in a Shigella-endemic location.

Methods

We applied a systems approach to retrospectively analyse serological responses to Shigella across endemic and non-endemic populations. We profiled serum samples collected from 44 individuals from the USA without previous exposure to Shigella and who were experimentally challenged with Shigella sonnei (non-endemic setting), and serum samples collected from 55 Peruvian army recruits (endemic setting). In the endemic setting, a subset of 37 samples collected from individuals infected with culture-confirmed Shigella flexneri 2a were divided into two groups: susceptible, which included individuals infected within 90 days of entering the camp (n=29); or resistant, which included individuals infected later than 90 days after entering the camp (n=8). We analysed Shigella-specific antibody isotype, subclass, and Fc receptor binding profiles across IpaB, IpaC, IpaD, and lipopolysaccharide from S flexneri 2a, 3a, and 6, and S sonnei, and O-specific polysaccharide (OSP) from S flexneri 2a and 3a and S sonnei. We also evaluated antibody-mediated complement deposition and innate immune cell activation. The main outcome of interest was the detection of antibody markers and functionality associated with protection against shigellosis in a high-burden endemic setting.

Findings

Adults with endemic exposure to Shigella possessed broad and functional antibody responses across polysaccharide, glycolipid, and protein antigens compared with individuals from non-endemic regions. In a setting with high Shigella burden, elevated levels of OSP-specific Fcα receptor (FcαR) binding antibodies were associated with resistance to shigellosis, whereas total OSP-specific IgA was not, suggesting a potentially unique functionality. OSP-specific FcαR binding IgA found in resistant individuals activated bactericidal neutrophil functions including phagocytosis, degranulation, and production of reactive oxygen species. Moreover, IgA depletion from resistant serum significantly reduced binding of OSP-specific antibodies to FcαR and antibody-mediated activation of neutrophils and monocytes.

Interpretation

Our findings suggest that OSP-specific functional IgA responses contribute to protective immunity against Shigella infection in a high-burden setting. These findings will assist in the development and evaluation of Shigella vaccines.

Funding

US National Institutes of Health.
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在志贺氏杆菌病流行区,免疫反应的决定因素可预测志贺氏杆菌病的发生:对抗体特征和功能的系统分析。
背景:志贺氏菌是导致全球 5 岁以下儿童中度或重度腹泻的第三大原因,也是导致 24-59 个月儿童腹泻的主要原因。在志贺氏杆菌流行地区,预防志贺氏杆菌感染和疾病的机制尚不确定。我们的目的是比较生活在志贺氏杆菌流行地区和非流行地区的人的志贺氏杆菌特异性抗体反应,并确定在志贺氏杆菌流行地区保护的相关因素:我们采用了一种系统方法,对志贺氏杆菌流行区和非流行区人群的血清反应进行了回顾性分析。我们分析了从美国 44 名以前未接触过志贺氏杆菌、但在实验中感染了松内志贺氏菌(非地方病)的人身上采集的血清样本,以及从 55 名秘鲁新兵(地方病)身上采集的血清样本。在地方病环境中,从感染了经培养证实的柔性志贺氏菌 2a 的个体中采集的 37 份样本被分为两组:易感组,包括进入营地后 90 天内感染的个体(29 人);耐受组,包括进入营地后 90 天后感染的个体(8 人)。我们分析了志贺氏杆菌特异性抗体的同型、亚类和 Fc 受体结合情况,包括 IpaB、IpaC、IpaD 和来自 S flexneri 2a、3a 和 6 以及 S sonnei 的脂多糖,以及来自 S flexneri 2a 和 3a 以及 S sonnei 的 O 特异性多糖 (OSP)。我们还评估了抗体介导的补体沉积和先天性免疫细胞活化。我们感兴趣的主要结果是,在高负担地方病环境中检测与志贺氏杆菌病保护相关的抗体标记物和功能:研究结果:与来自非志贺氏杆菌流行地区的个体相比,接触过志贺氏杆菌的成年人对多糖、糖脂和蛋白质抗原具有广泛的功能性抗体反应。在志贺氏杆菌负担较重的环境中,OSP特异性Fcα受体(FcαR)结合抗体水平的升高与志贺氏杆菌病的抵抗力有关,而OSP特异性IgA总量却与之无关,这表明OSP特异性IgA可能具有独特的功能。在耐药个体中发现的 OSP 特异性 FcαR 结合 IgA 激活了中性粒细胞的杀菌功能,包括吞噬、脱颗粒和产生活性氧。此外,从耐药血清中清除 IgA 能显著减少 OSP 特异性抗体与 FcαR 的结合以及抗体介导的中性粒细胞和单核细胞活化:我们的研究结果表明,OSP特异性功能性IgA反应有助于在高负担环境中对志贺氏杆菌感染产生保护性免疫。这些发现将有助于志贺氏杆菌疫苗的开发和评估:美国国立卫生研究院。
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来源期刊
Lancet Microbe
Lancet Microbe Multiple-
CiteScore
27.20
自引率
0.80%
发文量
278
审稿时长
6 weeks
期刊介绍: The Lancet Microbe is a gold open access journal committed to publishing content relevant to clinical microbiologists worldwide, with a focus on studies that advance clinical understanding, challenge the status quo, and advocate change in health policy.
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