Defining the role of lymphotoxin signaling in viral-induced lung immunopathology

 描述（由申请方提供）：肺部病理学是急性呼吸道病毒感染相关发病率和死亡率的重要原因。呼吸道病毒，如流感病毒，不仅对上皮细胞造成损伤，而且激活免疫防御机制。虽然这些免疫机制被用来破坏和清除感染的细胞，试图清除病毒，但它们也可以促进肺部病变。然而，在急性病毒感染期间调节保护和组织损伤之间平衡的关键细胞和分子机制仍然知之甚少。这种知识的缺乏严重限制了治疗这种疾病的新疗法的发展。因此，了解呼吸道病毒感染诱导肺损伤的基本机制对于开发用于治疗疾病的改进疗法至关重要。我们令人兴奋和有趣的初步结果表明，TNFR超家族的一个成员-本提案的总体目标是确定LTβR如何控制流感感染相关的肺损伤。我们的工作假设是，呼吸道上皮细胞中的LTβR信号传导抑制流感感染期间的粘液产生，从而导致病毒复制增加和肺损伤增加。为了验证这一假设，我们提出了两个具体目标。在目标1中，我们将使用生物化学和遗传学方法来确定LTβR信号传导对粘液产生和病毒复制的影响。在目的2中，我们将测试呼吸上皮细胞中的LTβR信号传导对于流感感染期间促进肺免疫病理学是必不可少的。我们认为，呼吸道上皮细胞中的LTβR信号促进病毒复制和诱导导致严重肺损伤的强效炎症反应。这些目标的实现将明确导致肺损伤的LTβ R依赖性机制。这项研究具有重要意义，因为它将更深入地了解调节病毒诱导的免疫病理学的机制，并将有助于开发新的免疫策略来控制呼吸道疾病。

 DESCRIPTION (provided by applicant): Lung pathology is a significant cause of the morbidity and mortality associated with acute respiratory virus infection. Respiratory viruses, such as influenza virus not only cause damage to the epithelium, but activate immune defense mechanisms. Although these immune mechanisms are employed to destroy and remove infected cells in an attempt to clear the virus, they can also promote lung pathology. However, the key cellular and molecular mechanisms that regulate the balance between protection and tissue damage during acute viral infection remain poorly understood. This lack of knowledge severely limits the development of novel therapies to treat the disease. Therefore, understanding the fundamental mechanisms whereby respiratory viral infection induces lung damage is critical for the development of improved therapies for treatment of disease. Our exciting and intriguing preliminary results suggest that the lymphotoxin beta receptor, LTßR, a member of the TNFR superfamily, promotes influenza-associated lung damage. The overall objective of this proposal is to define how LTβR controls lung damage associated with influenza infection. Our working hypothesis is that LTβR signaling in respiratory epithelial cells inhibits mucus production during influenza infection allowing for elevated viral replication and increased lung damage. To test this hypothesis, we propose two specific aims. In Aim 1, we will use biochemical and genetic approaches to determine the impact of LTβR signaling on mucus production and viral replication. In Aim 2, we will test that LTβR signaling in respiratory epitheial cells is essential to promote lung immunopathology during influenza infection. We propose that LTβR signaling in respiratory epithelial cells promotes viral replication and induction of potent inflammatory responses which cause severe lung damage. Completion of these aims will define the LTβR-dependent mechanisms that contribute to lung damage. The research proposed is significant, because it will provide a deeper understanding of the mechanisms regulating virus-induced immunopathology and will help in developing new immunotherapeutic strategies to control respiratory disease.