Host Defense and the Regulation of Interferon Production

描述（由申请人提供）：宿主暴露于微生物病原体（如病毒、细菌和真菌）会触发先天免疫反应的激活，包括I型干扰素（IFN）的产生，干扰素可以激发早期宿主防御机制，并激活涉及细胞毒性T细胞活性和抗体产生的适应性免疫反应。病原微生物的识别和先天免疫级联的触发已成为近年来研究的热点。最近人们特别关注toll样受体（TLRs）的作用，TLRs已成为树突状细胞和巨噬细胞主要表达的关键分子，负责识别病原微生物的保守成分（称为病原体相关分子模式- pamps），并触发IFN的产生。然而，最近发现也存在非常重要的不依赖tlr的机制来阻止病原体感染。在这些反应中起作用的是DExD/H解旋酶家族，它们似乎对有效防御病毒感染至关重要。然而，不依赖tlr的信号传导机制仍然很复杂，负责促进IFN产生的下游分子成分仍有待确定。在这里，我们已经分离出一种新的分子，它似乎在先天免疫信号的调节中起着重要作用，并且在对病原体感染的反应中对IFN的产生至关重要。为此，我们旨在研究该分子在先天免疫解旋酶作用中的重要性。从本质上讲，我们的目标是：1 .确定DExD/H解旋酶在对病原体感染的先天免疫中的重要性，包括其作用机制。II：为了潜在地确定参与病原体识别的DExD/H解旋酶介导的先天信号传导机制，我们已经有效地筛选了激活有效先天免疫所需的I型干扰素（IFN）产生的新分子。我们的目标是进一步表征这些分子在先天信号传导中的重要性，并确定它们的作用机制。这些目标将对先天免疫信号传导的机制产生重要的见解，并产生对新疫苗和免疫治疗策略产生有用的概念。

DESCRIPTION (provided by applicant): Host exposure to microbial pathogens such as viruses, bacteria and fungi trigger the activation of innate immune responses, including the production of type I interferon (IFN) that galvanize early host defense mechanisms as well as invigorate adaptive immune responses involving cytotoxic T cell activity and antibody production. The recognition of pathogenic microbes and the triggering of the innate immune cascade has become the subject of intense research over the past few years. Particular attention has recently focused on the role of the Toll-like receptors (TLRs), which have emerged as key molecules largely expressed by dendritic cells and macrophages, that are responsible for recognizing conserved components of pathogenic microorganisms (referred to as pathogen associated molecular patterns -PAMPs)- and which trigger the production of IFN. However, it has recently been discovered that critically important TLR-independent mechanisms also exist to thwart pathogen infection. Instrumental in these responses are a family of DExD/H helicases that appear critical for effective defense against virus infection. However, the mechanisms of TLR-independent signaling remain complex, with downstream molecular components responsible for facilitating the production of IFN remaining to be identified. Here, we have isolated a new molecule that appears to play a significant role in the regulation of innate immune signaling and which is critical for the production of IFN in response to pathogen infection. For this proposal we thus aim to study the importance of this molecule in innate immune helicase action. Essentially, we aim to: I: determine the importance of DExD/H helicases in innate immunity to pathogen infection, including mechanisms of action. II: To potentially determine the mechanisms of innate signaling mediated by the DExD/H helicases involved in pathogen recognition, we have effectively screened for novel molecules which activate the production of type I interferon (IFN), required for effective innate immunity. We aim to further characterize the importance of such molecules in innate signaling and aim to determine their mechanisms of action. These objectives will shed significant insight into the mechanisms of innate immune signaling and generate concepts useful for the generation of new vaccine and immunotherapeutic strategies. PUBLIC HEALTH RELEVANCE Our grant involves attempting to understand how the body recognizes diseases caused by viruses and bacteria. The proposal also aims to understand how the body induces an appropriate immune response following infection. By understanding these processes, we will gain insight into causes of disease and anticipate being able to develop new vaccine and therapeutic strategies. The study of LGP2 and STING and their interaction with other components in the pathway will provide significant insight about the molecular mechanism of RIG-I/MDA5-mediated IFN production and anti-viral innate immunity and thus is of high significance.