Mechanisms of protection against shigellosis in children

儿童志贺氏菌病的保护机​​制

• 批准号: 10530772
• 负责人: Marcela F Pasetti
• 金额: $ 77.84万
• 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/10530772
• 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; 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; Institutes; Knowledge; 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; Property; Protein Engineering; Proteins; Recombinants; Research; Resources; 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.

项目摘要 志贺菌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岁以下儿童 中等收入国家受影响最大。死亡率仅次于轮状病毒， 反复发作的疾病会导致终身残疾。志贺氏菌腹泻的发病率在第一次 在12至23个月大的幼儿中急剧增加，超过了所有其他病原体， 24个月后再次下降。母体免疫可能有助于早期屏蔽 婴儿患病，而随后的接触会建立适应性免疫力，降低患病风险 从2岁开始感染。关于志贺氏菌免疫力的大部分知识来自于 报告中没有关于成年人感染艾滋病毒的详细资料，但缺乏关于可预防儿童感染艾滋病毒的要素的详细资料。当前 最受欢迎和临床上最先进的疫苗概念，一种胃肠外递送的O-多糖蛋白 结合物，在现场研究中在<3岁的幼儿中失败。 我们的研究小组从生活在马拉维的母亲和婴儿的纵向队列中获得了临床标本 （在志贺氏菌流行的地方）从出生时到2岁，并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调查这些儿童志贺氏菌免疫的连续性， 定义母体抗体（Ab），有助于在生命的最初几个月内预防志贺氏菌病， 这些儿童在接触后获得的反应，降低了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。 我们的初步数据显示，由志贺氏菌蛋白特异性人抗体介导的强抗微生物免疫 (i.e. IpaB和VirG）;这些Ab与先天性免疫细胞接合，并且与免疫球蛋白相比具有不同的功能能力。 抗LPS抗体。在这项提案中，我们将测试的假设，蛋白质特异性免疫是至关重要的保护， 儿童志贺氏菌感染。在目标1中，我们将询问 使用系统血清学平台的系统性抗体以及T细胞和B细胞对志贺氏菌蛋白的应答， 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。所有 免疫学读数将在感染和非感染儿童之间进行纵向比较， 保护性免疫的相关因素。在目标3中，我们将运用目标1和2中获得的知识， 重组技术合理设计具有最大抗菌活性的蛋白特异性人单克隆抗体 使用免疫力最强的母亲的外周血细胞来发挥作用。 考虑到目前既没有疫苗预防志贺氏菌感染， 结果，特别是在幼儿中，也没有免疫疗法可以克服多种药物， 阻力G.拉根研究所和M. Pasetti在大学 马里兰州的医学博士保证了这一临床相关提案的成功，这将大大推动该领域的发展。