孟加拉国感染志贺氏菌的幼儿体内有限的 O-特异性多糖(OSP)特异性功能抗体反应

Biana Bernshtein, Julia A Zhiteneva, Jeshina Janardhanan, Chanchal Wagh, Meagan Kelly, Smriti Verma, Wonyeong Jung, Salima Raiyan Basher, Mohammad Ashraful Amin, Shakil Mahamud, Nazmul Hasan Rajib, Fahima Chowdhury, Ashraful Islam Khan, Richelle C. Charles, Peng Xu, Paul Kovac, Subhra Chakraborty, Robert W. Kaminski, Galit Alter, Taufiqur Rahman Bhuiyan, Firdausi Qadri, Edward T Ryan
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引用次数: 0

摘要

志贺氏杆菌病是导致全球五岁以下儿童腹泻死亡的第二大原因。目前,还没有针对志贺氏菌感染的广泛许可疫苗。以前的候选疫苗也未能为流行地区的幼儿提供保护。我们需要进一步了解生活在志贺氏杆菌流行地区的幼儿对志贺氏杆菌感染和严重志贺氏杆菌病的保护作用。在这里,我们采用功能性抗体分析方法来确定孟加拉国志贺氏菌流行地区的幼儿与经培养证实患有志贺氏菌病的老年人的志贺氏菌特异性抗体反应。我们分析了临床表现时和一年后采集的纵向血清样本中志贺氏杆菌特异性抗体的同型型、FcR结合和抗体介导的先天性免疫细胞活化。我们发现,与患者年龄无关,较高的初始志贺氏菌 O-特异性多糖(OSP)-特异性和蛋白-特异性 IgG 和 FcgR 结合水平与较轻的病情相关,但与年龄较大的患者相比,5 岁以下的患者对 OSP 和蛋白志贺氏菌抗原产生的类别转换、FcR 结合、功能性和持久性抗体反应不那么明显。我们以最大的群体为重点,发现只有在 5 岁以上的个体中才会显著诱导出功能性的柔性志贺氏菌 2a OSP 特异性反应,而且这些反应会促进单核细胞的吞噬和活化。我们的研究结果表明,在志贺氏杆菌流行的地区,患有志贺氏杆菌病的幼儿体内存在一种功能性抗体反应,这种反应不能最大限度地激活单核细胞;这种反应可能对促进随后先天性细胞清除志贺氏杆菌很重要,特别是通过招募和激活能够直接杀死志贺氏杆菌的多形核细胞。
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Limited O-specific polysaccharide (OSP)-specific functional antibody responses in young children with Shigella infection in Bangladesh
Shigellosis is the second leading cause of diarrheal death in children younger than five years of age globally. At present, there is no broadly licensed vaccine against shigella infection. Previous vaccine candidates have failed at providing protection for young children in endemic settings. Improved understanding of correlates of protection against Shigella infection and severe shigellosis in young children living in endemic settings is needed. Here, we applied a functional antibody profiling approach to define Shigella-specific antibody responses in young children versus older individuals with culture-confirmed shigellosis in Bangladesh, a Shigella endemic area. We analyzed Shigella-specific antibody isotypes, FcR binding and antibody-mediated innate immune cell activation in longitudinal serum samples collected at clinical presentation and up to 1 year later. We found that higher initial Shigella O-specific polysaccharide (OSP)-specific and protein-specific IgG and FcgR binding levels correlated with less severe disease regardless of patient age, but that individuals under 5 years of age developed a less prominent class switched, FcR-binding, functional and durable antibody response against both OSP and protein Shigella antigens than older individuals. Focusing on the largest cohort, we found that functional S. flexneri 2a OSP-specific responses were significantly induced only in individuals over age 5 years, and that these responses promoted monocyte phagocytosis and activation. Our findings suggest that in a Shigella endemic region, young children with shigellosis harbor a functional antibody response that fails to maximally activate monocytes; such a response may be important in facilitating subsequent innate cell clearance of Shigella, especially via recruitment and activation of polymorphonuclear cells capable of directly killing Shigella.
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