Mechanisms of protection against shigellosis in children

儿童志贺氏菌病的保护机​​制

• 批准号: 10641951
• 负责人: Marcela F Pasetti
• 金额: $ 76.48万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-09 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641951
• 关键词: 2 year old; 3 year old; 5 year old; Adult; Affect; Age; Age Months; Antibiotic Resistance; Antibiotics; Antibodies; Antigens; Antimicrobial Resistance; B-Lymphocytes; Biological Assay; Biophysics; Birth; Blood Cells; Cells; Cellular Immunity; Cessation of life; Child; Child Care; Childhood; Clinical; Clinical Data; Data; Developed Countries; Development; Diarrhea; Disease; Disease Outbreaks; Drug resistance; Dysentery; Elements; Engineering; Evolution; Exhibits; Exposure to; Goals; Growth; Human; Human Engineering; Human Milk; Immune; Immune response; Immunity; Immunoglobulin A; Immunologic Markers; Immunologics; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Incidence; Infant; Infection; Infection prevention; Invaded; Knowledge; Knowledge acquisition; Life; Longitudinal cohort; Malawi; Maps; Maryland; Maternal antibody; Maternally-Acquired Immunity; Mediating; Monitor; Monoclonal Antibodies; Mothers; Multi-Drug Resistance; Mus; Organism; Pediatric cohort; Perinatal Infection; Phagocytes; Phagocytosis; Placenta; Plasmids; Polysaccharides; Predisposition; Property; Protein Engineering; Proteins; Recombinants; Research; Resources; Risk Reduction; Rotavirus; Serology; Serum; Shigella; Shigella Infections; Specificity; Specimen; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Toddler; Umbilical Cord Blood; Universities; Vaccine Therapy; Vaccines; Virulent; Vulnerable Populations; Work; acquired immunity; adaptive immunity; antibody transfer; antimicrobial; clinically relevant; cohort; design; diarrheal disease; disability; efficacy testing; enteric infection; epidemiology study; experience; field study; human monoclonal antibodies; in vitro Assay; in vivo; infection risk; innovation; longitudinal analysis; low and middle-income countries; monocyte; mortality; neutrophil; novel; novel therapeutics; pathogen; prevent; protective efficacy; resistant strain; response; success; tool; trend; vaccine development

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.

项目概要 志贺氏菌属是全球腹泻和痢疾的主要原因。生活在低收入和低收入地区的<5岁儿童 中等收入国家受影响最严重。腹泻病原体中死亡率仅次于轮状病毒， 疾病反复发作会导致终身残疾。志贺氏菌腹泻的发生率在第一阶段较低 12 至 23 个月大的幼儿中，感染率急剧上升，超过所有其他病原体，并且 24个月后再次下降。母体免疫力可能有助于早期屏蔽 幼儿患病，而随后的暴露会建立适应性免疫，从而降低患病风险 2岁起感染。关于志贺氏菌免疫的大部分知识都来自以下研究： 成人，而缺乏有关预防儿童感染的元素的详细信息。目前的 最受欢迎且临床上最先进的疫苗概念，一种肠胃外递送的 O-多糖蛋白 结合物，在<3岁的幼儿现场研究中失败了。 我们的小组可以从居住在马拉维的母亲和婴儿的纵向队列中获取临床标本 （志贺氏菌为地方性病）从出生时到 2 岁，对婴儿志贺氏菌感染进行监测。 我们建议以前所未有的深度询问这些儿童的志贺氏菌免疫力的连续性，以 定义有助于在生命最初几个月预防志贺氏菌病的母体抗体 (Ab) 和免疫系统 这些儿童在接触后获得的反应可降低 2 岁后感染的风险。 将在来自马拉维的儿童的单独纵向队列中监测 5 岁以下的抗体累积情况。 我们的初步数据揭示了志贺氏菌蛋白特异性人类抗体介导的强大抗微生物免疫力 （即 IpaB 和 VirG）；与先天免疫细胞相比，这些抗体具有独特的功能能力 抗 LPS 的抗体。在本提案中，我们将检验以下假设：蛋白质特异性免疫对于保护病毒至关重要。 儿童抵抗志贺氏菌感染。在目标 1 中，我们将探讨以下物质的生物物理和功能特性： 使用系统血清学平台进行全身抗体检测，以及 T 细胞和 B 细胞对志贺氏菌蛋白的反应 儿科队列。在目标 2 中，系统血清学方法将用于表征母乳中的抗体。全部 将纵向比较感染儿童和未感染儿童的免疫学读数，以揭开真相 保护性免疫的相关性。在目标 3 中，我们将应用在目标 1 和 2 中获得的知识以及新颖的知识 重组技术合理设计具有最大抗菌能力的蛋白质特异性人单克隆抗体 使用免疫力最高的母亲的外周血细胞发挥功能。 鉴于目前尚无预防志贺氏菌感染及其破坏性的疫苗，这一应用是及时的。 后果，特别是对幼儿，也没有可以克服多种药物的免疫疗法 反抗。拉贡研究所的 G. Alter 和大学的 M. Pasetti 的协同努力和独特资源 马里兰州保证了这一临床相关提案的成功，这将极大地推进该领域的发展。