Regulating heart disease: the adjuvant effect of viral infection.

描述(申请人提供)：心血管疾病是美国的头号杀手。炎症性心脏病(心肌炎)的发病率和严重程度在男性中较高。前炎性细胞因子在心肌炎的发生发展中起关键作用。最近的证据表明，感染、先天Toll样受体(TLR)信号与心脏病增加之间存在联系。已知佐剂可在小鼠中诱发炎症性疾病，如实验性自身免疫性心肌炎(EAM)，尽管确切的机制尚不清楚。佐剂在先天免疫反应中发挥作用，增加促炎细胞因子，如白介素1和白介素12，导致辅助性T细胞(Th)1型炎症反应。PI最近的研究表明，柯萨奇病毒B3(CVB3)感染通过与EAM佐剂相似的机制诱导小鼠炎症性心脏病。我们发现，TLR4缺陷小鼠显著降低了急性心肌炎和心脏中IL-1的水平，并增加了Th1抑制受体TIM-3的水平，这表明TLR4信号在先天性免疫期间减少了TIM-3的表达，从而导致心脏炎症的增加。在CVB3感染的先天免疫应答中阻断TIM-3会增加抗原提呈细胞(ARC)上TLR4的表达，这表明TIM-3信号转导降低了CVB3感染后ARC上TLR4的表达。我们的结果表明，TLR4和TIM-3信号之间的相互作用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，说明病毒感染在先天免疫反应中的作用类似于佐剂，从而增加了男性急性和慢性心肌炎。在这项提案中，我们将使用CVB3诱导的心肌炎的小鼠模型来研究以下问题。目的1)男性CVB3感染后心肌炎的增加是由TLR4特异性介导的，还是其他TLR信号通路参与的？目的2)促炎症细胞因子(如IL-1)是否通过类似病毒的机制(即增加TLR4和降低TIM-3)增加心肌炎？目的3)活动性病毒感染是否是心肌炎发生所必需的？佐剂是否使用与病毒相同的机制来增加炎症？ 与公共健康相关：在美国，心脏病是主要的死亡原因。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.