Innate lymphocyte responses to early-life infections

点击翻译按钮获取中文摘要

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.