Innate lymphocyte responses to early-life infections

项目摘要 葡萄球菌是新生儿重症监护病房卫生保健相关感染的主要原因 全球范围内皮肤和软组织感染的主要原因。除了引起脓疱病外， 儿童中最常见的细菌感染，葡萄球菌可导致危及生命的情况，包括 脓毒症和葡萄球菌烫伤皮肤综合征。然而，目前还没有有效的疫苗可用 针对葡萄球菌，防止母婴免疫，并出现抗生素耐药性 阻碍了标准治疗。因此，有必要了解免疫系统是如何反应的 对早期生命中葡萄球菌感染的影响。而先天免疫细胞利用生殖线编码的受体来检测 保守的病原体相关分子模式，适应细胞重组受体基因产生 广泛的抗原特异性，推迟了获得性免疫的出现。随着发展， 获得性免疫细胞需要在次级淋巴器官内通过抗原介导的激活来表达 趋化因子受体和整合素是组织归巢和产生效应细胞因子或抗体所必需的。 因此，在生命早期，适应性免疫细胞在大多数屏障组织中大量缺失，而不是 有先天淋巴样细胞(ILCs)和先天T细胞。两者主要定位于组织并迅速释放 细胞因子是由于发育过程中获得效应器特征而产生的。而ILC缺乏重组抗原 受体，先天的T细胞表达半不变的T细胞受体，以类似的方式限制其抗原范围 先天免疫受体。尽管这些淋巴细胞在免疫记忆建立之前就出现了 并在早期生命中大量存在，但对它们在这一时期对免疫的贡献仍知之甚少。这个 这项建议的主要目标是确定先天和先天样淋巴细胞在早期免疫中的作用， 这将通过1)开发早期小鼠感染模型，2)建立 在这些模型中对小鼠先天和先天类淋巴细胞的影响，以及3)评估人类体内的反应 利用人源化小鼠的先天和先天的淋巴细胞。将最先进的方法与 免疫学、遗传学和生物信息学，这一高度创新的项目将进一步加深我们对早期- 生命免疫力，并导致新疗法的发展。

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.