Innate lymphocyte responses to early-life infections

先天淋巴细胞对生命早期感染的反应

• 批准号: 10716092
• 负责人: Michael George Constantinides
• 金额: $ 45.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716092
• 关键词: Antibodies; Antigen Receptors; Antigens; Bacteria; Bacterial Infections; Bioinformatics; Cells; Characteristics; Child; Development; Genetic; Genus staphylococcus; Goals; Homing; Human; Immune; Immune system; Immunity; Immunologic Memory; Immunologic Receptors; Immunology; Impetigo; Infection; Integrins; Life; Lymphocyte; Lymphoid Cell; Mediating; Modeling; Molecular; Mus; Neonatal; Neonatal Intensive Care Units; Pattern; Population; Receptor Gene; Role; Sepsis; Skin Tissue; Soft Tissue Infections; Specificity; Staphylococcal Infections; Staphylococcal Scalded Skin Syndrome; T-Cell Receptor; T-Lymphocyte; Tissues; adaptive immunity; chemokine receptor; cytokine; emerging antibiotic resistance; healthcare-associated infections; humanized mouse; in vivo; innovation; maternal vaccination; novel; novel therapeutics; pathogen; prevent; receptor; response; secondary lymphoid organ; standard care; vaccine access

Project Summary Staphylococcus bacteria are the primary cause of healthcare-associated infections in neonatal intensive care units and the leading cause of skin and soft tissue infections worldwide. In addition to causing impetigo, the most common bacterial infection in children, Staphylococcus can result in life-threatening conditions, including sepsis and Staphylococcal scalded skin syndrome. However, there are currently no effective vaccines available for Staphylococcus bacteria, preventing maternal immunization, and the emergence of antibiotic resistance impedes standard treatments. Consequently, there is a need to understand how the immune system responds to Staphylococcal infections in early life. While innate immune cells utilize germline-encoded receptors to detect conserved pathogen-associated molecular patterns, adaptive cells recombine receptor genes to generate a broad range of antigen specificities, which delays the emergence of adaptive immunity. Following development, adaptive immune cells require antigen-mediated activation within secondary lymphoid organs to express the chemokine receptors and integrins necessary for tissue homing and produce effector cytokines or antibodies. Consequently, adaptive immune cells are largely absent from most barrier tissues in early life, which instead harbor innate lymphoid cells (ILCs) and innate-like T cells. Both primarily localize to tissues and rapidly release cytokines due to their developmental acquisition of effector characteristics. While ILCs lack recombined antigen receptors, innate-like T cells express semi-invariant T cell receptors that limit their antigenic range analogously to innate immune receptors. Though these lymphocytes arise prior to the establishment of immunologic memory and are abundant in early life, their contributions to immunity during this period remain poorly understood. The primary goal of this proposal is to determine the role of innate and innate-like lymphocytes in early-life immunity, which will be accomplished by 1) developing early-life murine infection models, 2) establishing the contributions of murine innate and innate-like lymphocytes in these models, and 3) assessing the in vivo responses of human innate and innate-like lymphocytes utilizing humanized mice. Combining state-of-the-art approaches from immunology, genetics, and bioinformatics, this highly innovative project will further our understanding of early- life immunity and lead to the development of novel therapeutics.

项目摘要 葡萄球菌是新生儿重症监护病房医疗相关感染的主要原因 护理单位和全球皮肤和软组织感染的主要原因。除了引起脓疱疹外， 葡萄球菌是儿童最常见的细菌感染，可导致危及生命的疾病，包括 脓毒症和葡萄球菌烫伤样皮肤综合征。但目前尚无有效疫苗 针对葡萄球菌属细菌，预防母体免疫，并出现抗生素耐药性 妨碍了标准治疗因此，有必要了解免疫系统如何响应 早期的葡萄球菌感染虽然先天免疫细胞利用生殖细胞编码的受体来检测 保守的病原体相关分子模式，适应性细胞重组受体基因， 广泛的抗原特异性，这延迟了适应性免疫的出现。随着发展， 适应性免疫细胞需要在次级淋巴器官内抗原介导的活化来表达 趋化因子受体和组织归巢所必需的整联蛋白，并产生效应细胞因子或抗体。 因此，适应性免疫细胞在生命早期在大多数屏障组织中基本上不存在， 具有先天淋巴细胞（ILC）和先天样T细胞。两者都主要定位于组织并迅速释放 细胞因子由于其效应子特征的发育获得而增加。ILC缺乏重组抗原 受体，先天样T细胞表达半不变的T细胞受体，类似地限制其抗原范围 与先天免疫受体有关。虽然这些淋巴细胞在免疫记忆建立之前就已经出现， 在生命早期大量存在，但对这一时期它们对免疫力的贡献仍知之甚少。的 该提议的主要目标是确定先天和先天样淋巴细胞在早期生命免疫中的作用， 这将通过1）开发早期小鼠感染模型，2）建立 的小鼠先天和先天样淋巴细胞在这些模型中，和3）评估人的体内反应， 利用人源化小鼠的先天和先天样淋巴细胞。结合最先进的方法， 免疫学，遗传学和生物信息学，这个高度创新的项目将进一步我们对早期- 生命免疫，并导致新疗法的发展。