Regulating heart disease: the adjuvant effect of viral infection.

描述（由申请人提供）：心血管疾病是美国的头号杀手。男子患炎性心脏病（心肌炎）的发病率和严重程度较高。促炎细胞因子对心肌炎的发展至关重要。最近的证据表明，感染，先天Toll样受体（TLR）信号传导和心脏病增加之间存在联系。已知佐剂可诱导炎症性疾病，如小鼠实验性自身免疫性心肌炎（EAM），但确切机制尚不清楚。佐剂在先天免疫应答期间起作用以增加促炎细胞因子，例如白细胞介素（IL）-1和IL- 12，导致T辅助细胞（Th）1型炎症应答。PI最近的研究表明，柯萨奇病毒B3（CVB 3）感染通过与EAM中佐剂相似的机制诱导小鼠炎症性心脏病。我们发现，TLR 4缺陷小鼠的急性心肌炎和心脏中的IL-1水平显着降低，Th 1抑制性受体Tim-3的水平增加，表明TLR 4信号减少Tim-3的表达在先天免疫导致心脏炎症增加。在对CVB 3感染的先天免疫应答期间阻断Tim-3增加了抗原呈递细胞（ARC）上的TLR 4表达，表明Tim-3信号传导降低了CVB 3感染后ARC上的TLR 4表达。我们的研究结果表明，TLR 4和Tim-3信号之间的串扰调节病毒感染后炎症的严重程度。这些结果提供了一种机制，病毒感染如何在先天免疫反应中起类似于佐剂的作用，以增加男性的急性和慢性心肌炎。在这个提议中，我们将使用CVB 3诱导的心肌炎的小鼠模型来研究以下问题。目的1）CVB 3感染后男性心肌炎的增加是否由TLR 4特异性介导，或是否涉及其他TLR信号通路？目的2）促炎细胞因子（如IL-1）是否使用类似于病毒的机制（即增加TLR 4和减少Tim-3）增加心肌炎？目的3）活动性病毒感染是心肌炎发生的必要条件吗？佐剂是否使用与病毒相同的机制增加炎症？ 与公共卫生的相关性：心脏病是美国的主要死亡原因。这项建议将研究先天免疫过程中病毒感染对心脏病发展的辅助作用。

DESCRIPTION (provided by applicant): Cardiovascular disease is the number one killer in the US. The incidence and severity of inflammatory heart disease (myocarditis) is higher among men. Proinflammatory cytokines are critical for the development of myocarditis. Recent evidence suggests a link between infections, innate Toll-like receptor (TLR) signaling and increased heart disease. Adjuvants are known to induce inflammatory diseases such as experimental autoimmune myocarditis (EAM) in mice, although the precise mechanisms are unclear. Adjuvants work during the innate immune response to increase proinflammatory cytokines, such as interleukin (IL)-1 and IL- 12, resulting in a T helper (Th)1-type inflammatory response. Recent studies by the PI suggest that coxsackievirus B3 (CVB3) infection induces inflammatory heart disease in mice by mechanisms similar to adjuvant in EAM. We show that TLR4 deficient mice have significantly reduced acute myocarditis and IL-1 levels in the heart and increased levels of the Th1 inhibitory receptor Tim-3, indicating that TLR4 signaling reduces Tim-3 expression during innate immunity resulting in increased inflammation in the heart. Blocking Tim-3 during the innate immune response to CVB3 infection increases TLR4 expression on antigen presenting cells (ARC), indicating that Tim-3 signaling reduces TLR4 expression on ARC following CVB3 infection. Our results demonstrate that cross-talk between TLR4 and Tim-3 signaling regulates the severity of inflammation following viral infection. These results provide a mechanism for how viral infections act similar to adjuvants during the innate immune response to increase acute and chronic myocarditis in males. In this proposal we will examine the following questions using the mouse model of CVB3-induced myocarditis. Aim 1) Is increased myocarditis in males following CVB3 infection mediated specifically by TLR4, or are other TLR signaling pathways involved? Aim 2) Do proinflammatory cytokines (e.g. IL-1) increase myocarditis using mechanisms similar to virus (i.e. increase TLR4 and decrease Tim-3)? Aim 3) Is active viral infection necessary for the development of myocarditis? Do adjuvants increase inflammation using the same mechanisms as virus? Relevance to Public Health: Heart disease is the leading cause of death in the US. This proposal will examine the adjuvant effect of viral infection during innate immunity on the development of heart disease.