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 葡萄球菌细菌是新生儿密集型医疗相关感染的主要原因 全球护理单位和皮肤和软组织感染的主要原因。除了引起impetigo之外， 儿童中最常见的细菌感染，葡萄球菌可能导致威胁生命的状况，包括 败血症和葡萄球菌烧结的皮肤综合征。但是，目前尚无有效的疫苗 对于葡萄球菌细菌，预防母体免疫和抗生素耐药性的出现 阻碍标准治疗。因此，有必要了解免疫系统的反应 早期感染葡萄球菌感染。而先天免疫细胞利用种系编码的受体来检测 保守的病原体相关分子模式，适应性细胞重组受体基因产生A 广泛的抗原特异性延迟了自适应免疫的出现。在发展之后， 自适应免疫细胞需要二次淋巴机器人内抗原介导的激活表达 趋化因子受体和整联蛋白需要组织归巢并产生效应细胞因子或抗体。 因此，在早期的大多数屏障组织中，自适应免疫细胞在很大程度上不存在 携带先天淋巴样细胞（ILC）和先天的T细胞。既主要位于组织，又快速释放 细胞因子由于其发育效果特征的发育获得。而ILC缺乏重新组合的抗原 受体，先天的T细胞表达半不变的T细胞受体，该受体类似地限制其抗原范围 先天免疫受体。尽管这些淋巴细胞是在建立免疫记忆之前出现的 并且在早期的生活中充实，在此期间，它们对免疫的贡献仍然很少。这 该提案的主要目标是确定先天和先天性淋巴细胞在早期免疫中的作用， 这将通过1）开发早期生命的鼠感染模型，2）建立贡献 这些模型中的鼠生和先天性淋巴细胞的含量，以及3）评估人的体内反应 使用人源化小鼠的先天和先天性淋巴细胞。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了解我们对早期的理解 生命的免疫力并导致新型治疗学的发展。