Immune Response Consortium: Integrated In Silico, In Vitro, and In Vivo Studies

描述（由申请人提供）：由细胞内病原体引起的全球疾病负担仍然是生物医学界面临的巨大挑战之一。这些病原体和它们的基因改造变种也可能被用于生物恐怖主义行动。免疫系统的先天和适应性成分使生物体能够靶向并消除病原体或被其感染的细胞。对细胞内病原体的适应性免疫反应的激活是由T细胞精心安排的。这个项目的一个中心假设是，了解T细胞如何以非凡的敏感性检测抗原，以及如何调节T细胞的激活，是制定对抗感染、自身免疫性疾病和生物恐怖主义制剂的合理方案的关键。特别是，这方面的知识应有助于开发疫苗和新型疗法，以治疗可能致命的感染。对涉及T细胞活化的各种过程的综合机制理解提出了艰巨的挑战。一个挑战是，T细胞激活涉及的过程发生在广泛的长度和时间尺度上，从分子识别事件（发生在毫秒时间尺度上）到响应感染的特定T细胞克隆的增殖（发生在几天后）。第二个挑战是，这些过程中的每一个都是涉及许多分子和/或细胞成分的集体动态事件的结果，仅通过检查少数实验报告很难直观地理解机制。这个项目的目的是将一组科学家（免疫反应联盟）聚集在一起，他们致力于对T细胞在对真实病原体的反应中激活的多尺度过程进行综合理解。我们将通过建立一种新的范式来实现这一目标，在这种范式中，团队的所有成员将使用将物理科学和生命科学结合在一起的方法来研究同一生物过程的不同方面。计算研究（植根于物理科学）将与体外和体内遗传和生化实验无缝结合，以了解对NIH B类病原体单核细胞增生李斯特菌的适应性免疫反应。

DESCRIPTION (provided by applicant): The global burden of disease caused by intracellular pathogens remains one of the great challenges facing the biomedical community. Such pathogens and their engineered variants could also be employed in acts of bioterrorism. The innate and adaptive components of the immune system enable organisms to target and eliminate pathogens or cells infected with them. Activation of the adaptive immune response to intracellular pathogens is orchestrated by T cells. A central hypothesis of this program project is that understanding how T cells detect antigen with extraordinary sensitivity and how T cell activation is regulated is a key for developing rational protocols for combating infections, autoimmune disorders, and bioterrorism agents. In particular, this knowledge should lead to the development of vaccines and novel forms of therapeutics to treat potentially deadly infections. Developing an integrated mechanistic understanding of the various processes involved in T cell activation presents formidable challenges. One challenge is that T cell activation involves processes that occur over a wide spectrum of length and time scales ranging from molecular recognition events (that occur on millisecond time scales) to proliferation of specific T cell clones in response to infection (which happens after several days). A second challenge is that each of these processes is the result of collective dynamic events involving many molecular and/or cellular components, and it is difficult to intuit mechanistic understanding by examining only a few experimental reporters. The purpose of this program project is to bring together a team of scientists (the Immune Response Consortium) who are committed to developing an integrated understanding of the multiscale processes pertinent to T cell activation in response to a real pathogen. We will pursue this goal by building on a new paradigm where all members of the team will work on different aspects of the same biological process using methods that bring together the physical and life sciences. Computational studies (rooted in the physical sciences) will be seamlessly integrated with in vitro and in vivo genetic and biochemical experiments to understand the adaptive immune response to the NIH Category B pathogen, Listeria monocytogenes.