Mechanisms of protection against shigellosis in children

项目总结 志贺氏菌属是全球腹泻和痢疾的主要原因。5岁的儿童生活在低地和 中等收入国家受影响最大。在腹泻病原体中，死亡率仅次于轮状病毒， 反复发作的疾病会导致终生残疾。志贺氏菌腹泻发病率在第一季度较低。 在12到23个月大的学步儿童中，这种疾病急剧增加，超过了所有其他病原体 在24个月后再次下降。母体免疫可能有助于早期屏蔽 婴幼儿的疾病，而随后的暴露建立了一种适应性免疫，降低了患上 从2岁开始感染。关于志贺氏菌免疫力的大部分已知来自于 虽然缺乏关于可预防儿童感染的因素的详细信息，但仍有许多儿童感染儿童的信息。目前的 最受欢迎和临床最先进的疫苗概念--一种非肠道注射的O-多糖蛋白 在3岁以下儿童的实地研究中失败了。 我们小组获得了居住在马拉维的母婴纵向队列的临床样本 (志贺氏菌流行的地方)从出生时到2岁，对婴儿进行志贺氏菌感染监测。 我们建议以前所未有的深度询问这些儿童中志贺氏菌免疫的连续体，以 定义母体抗体(Ab)，帮助预防出生后头几个月的志贺氏菌病和免疫 这些儿童在暴露后获得的反应可降低2岁后感染的风险。 将在马拉维单独的纵向队列中监测5岁以下儿童抗体的累积情况。 我们的初步数据显示，志贺氏菌蛋白的特异性人源抗体具有很强的抗微生物免疫作用 (即IPAB和Virg)；这些抗体与先天免疫细胞结合，与 AB抗内毒素。在这项提案中，我们将检验蛋白质特异性免疫对保护 儿童预防志贺氏菌感染。在目标1中，我们将询问生物物理和功能特性 使用系统血清学平台的系统抗体以及T和B细胞对志贺氏菌蛋白的反应 儿科队列。在目标2中，将使用系统血清学方法来鉴定母乳中的抗体。全 免疫读数将在感染和未感染的儿童之间进行纵向比较，以揭开面纱 保护性免疫的相关因素。在目标3中，我们将应用在目标1和2以及小说中学到的知识 合理设计具有最大抗菌力的蛋白质特异性人源单抗的重组技术 使用免疫力最高的母亲的外周血细胞。 考虑到目前还没有预防志贺氏菌感染及其破坏性的疫苗，这种应用是及时的 后果，特别是在幼儿中，也不是可以克服多种药物的免疫疗法 抵抗。拉贡研究所的G.Alter和大学的M.Pasetti的协同努力和独特资源 确保了这一临床相关提案的成功，这将极大地推动该领域的发展。

PROJECT SUMMARY Shigella spp. are a major global cause of diarrhea and dysentery. Children <5 years of age living in low- and middle-income countries are the most affected. Mortality is second only to rotavirus among diarrheal pathogens, and repeated bouts of disease cause lifelong disability. The incidence of Shigella diarrhea is low during the first year of life, increases dramatically in toddlers 12- to 23-month-old, surpassing all other pathogens, and decreases once again after 24 months of age. Maternal immunity likely contributes to the early shielding of disease in young infants, while subsequent exposure establishes an adaptive immunity that reduces risk of infection from 2 years of age onwards. Much of what is known about Shigella immunity comes from studies in adults, while detailed information on elements that can prevent infection in children is lacking. The currently favored and most clinically advanced vaccine concept, a parenterally delivered O-polysaccharide-protein conjugate, has failed in young children <3 years of age in field studies. Our group has access to clinical specimens from a longitudinal cohort of mothers and infants living in Malawi (where Shigella is endemic) from the time of birth to 2 years of age, with infant surveillance for Shigella infection. We propose to interrogate with unprecedented depth the continuum of Shigella immunity in these children to define maternal antibodies (Ab) that help prevent shigellosis during the first months of life and the immune responses these children acquire post exposure that reduces the risk of infection after the 2-year-old mark. Accrual of Ab up to 5 years of age will be monitored in a separate longitudinal cohort of children from Malawi. Our preliminary data revealed strong anti-microbial immunity mediated by human Ab specific for Shigella proteins (i.e. IpaB and VirG); these Ab engage innate immune cells and have distinct functional capabilities compared to Ab against LPS. In this proposal, we will test the hypothesis that protein-specific immunity is critical to protect children against Shigella infection. In Aim 1, we will interrogate the biophysical and functional properties of systemic Ab using a Systems Serology platform as well as T- and B-cell responses to Shigella proteins in the pediatric cohorts. In Aim 2, the Systems Serology approach will be used to characterize Ab in breast milk. All immunological readouts will be compared longitudinally between infected and non-infected children to unmask correlates of protective immunity. In Aim 3, we will apply the knowledge acquired in Aims 1 and 2 and novel recombinant technology to rationally engineer protein-specific human monoclonal Ab with maximal antimicrobial function using peripheral blood cells from the mothers with the highest immunity. This application is timely, given that there are neither vaccines to prevent Shigella infection and its devastating consequences, particularly in young children, nor immune therapeutics that could overcome multi-drug resistance. The synergistic effort and unique resources of G. Alter at Ragon Institute and M. Pasetti at University of Maryland assures the success of this clinically relevant proposal, which will greatly advance the field.