Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Lancet Microbe. 2024 Oct;5(10):100889. doi: 10.1016/S2666-5247(24)00112-5. Epub 2024 Aug 5.
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.
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.
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.
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.
US National Institutes of Health.
志贺菌是导致全球 5 岁以下儿童中度或重度腹泻的第三大主要原因，也是 24-59 个月儿童腹泻的主要原因。在流行地区，针对志贺菌感染和疾病的保护机制尚不清楚。本研究旨在比较生活在志贺菌流行区和非流行区的个体的志贺菌特异性抗体反应，并确定在志贺菌流行地区的保护相关因素。
我们采用系统方法回顾性分析了来自美国的 44 名无志贺菌既往暴露史且经志贺菌 sonnei 实验性感染的个体（非流行地区）和来自秘鲁军队新兵的血清样本（流行地区）的血清样本。在流行地区，从经培养证实感染志贺菌 flexneri 2a 的 37 名个体中采集的亚组样本分为两组：易感性组，包括在进入营地后 90 天内感染的个体（n=29）；或耐药组，包括在进入营地后 90 天后感染的个体（n=8）。我们分析了 IpaB、IpaC、IpaD 和 lipopolysaccharide 来自 S flexneri 2a、3a 和 6，以及 S sonnei 的 IpaB、IpaC、IpaD 和 lipopolysaccharide 来自 S flexneri 2a 和 3a 和 S sonnei 的血清样本。我们还评估了抗体介导的补体沉积和固有免疫细胞激活。主要观察终点是在高负担流行地区检测与抗志贺菌病相关的抗体标志物和功能。
与非流行地区的个体相比，流行地区暴露于志贺菌的成年人对多糖、糖脂和蛋白抗原具有广泛而有功能的抗体反应。在志贺菌高负担的环境中，高水平的 OSP 特异性 Fcα 受体（FcαR）结合抗体与抗志贺菌病的耐药性相关，而总 OSP 特异性 IgA 则没有，表明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 可激活杀菌性中性粒细胞功能，包括吞噬作用、脱颗粒作用和产生活性氧。此外，从耐药血清中去除 IgA 可显著降低 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的激活。
我们的研究结果表明，在高负担环境中，OSP 特异性功能性 IgA 反应有助于对志贺菌感染的保护性免疫。这些发现将有助于志贺菌疫苗的开发和评估。
美国国立卫生研究院。
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