Regulating heart disease: the adjuvant effect of viral infection.

调节心脏病：病毒感染的辅助作用。

基本信息

批准号：
7188309
负责人：
DeLisa Fairweather
金额：
$ 40.93万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7188309
关键词：
Acute Acute Myocarditis Adaptor Signaling Protein Address Adjuvant Antigen-Presenting Cells Appendix Ascaridil Autoimmune Process Autoimmunity CD80 gene Cardiovascular Diseases Cause of Death Cell Count Cells Cessation of life Chronic Coxsackie Viruses Cytokine Receptors Cytokine Signaling Development Dilated Cardiomyopathy Disease Equilibrium Female Figs - dietary Genes Goals Heart Heart Diseases Hour Human IRF3 gene Immune Immune response Immunity Immunization Immunoglobulins Immunology Inbred BALB C Mice Incidence Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-12 Interleukin-18 Interleukin-6 Interleukins Knowledge Ligands Link MHC Class II Genes Mediating Mediator of activation protein Modeling Mucins Mus Myocarditis Natural Immunity Numbers Paper Pathway interactions Patients Phosphotransferases Play Principal Investigator Public Health Receptor Signaling Recruitment Activity Regulation Research Research Personnel Role Severities Signal Pathway Signal Transduction T-Lymphocyte TLR2 gene TLR3 gene TLR4 gene TLR7 gene TNF gene Tissues Toll-like receptors Viral Virus Virus Diseases Work chemokine cytokine macrophage male mast cell men mouse model novel prevent programs protein activation receptor research study toll-like receptor 4 transcription factor

项目摘要

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.

描述（由申请人提供）：心血管疾病是美国排名第一的杀手。男性中炎症性心脏病（心肌炎）的发病率和严重程度更高。促炎细胞因子对于心肌炎的发展至关重要。最近的证据表明，感染，先天性收费受体（TLR）信号传导与心脏病增加之间的联系。已知佐剂会诱导炎症性疾病，例如小鼠的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期间起作用，以增加促炎细胞因子，例如白介素（IL）-1和IL-12，从而导致T助手（TH）1型炎症反应。 PI的最新研究表明，Coxsackievivirus B3（CVB3）感染通过类似于EAM辅助的机制诱导小鼠炎症性心脏病。我们表明，TLR4缺乏的小鼠在心脏中显着降低了急性心肌炎和IL-1水平，而Th1抑制性受体TIM-3的水平升高，表明TLR4信号传导降低了TIM-3在先天免疫力期间降低了心脏炎症增加。在对CVB3感染的先天免疫反应期间阻止TIM-3会增加抗原呈递细胞（ARC）的TLR4表达，这表明TIM-3信号传导在CVB3感染后降低了TLR4的表达。我们的结果表明，TLR4和TIM-3信号之间的串扰调节病毒感染后炎症的严重程度。这些结果为病毒感染在先天免疫反应期间与佐剂的作用相似，以增加男性急性和慢性心肌炎。在此提案中，我们将使用CVB3诱导的心肌炎的小鼠模型检查以下问题。 AIM 1）CVB3感染是由TLR4专门介导的，还是其他TLR信号通路涉及的CVB3感染后，男性心肌炎是否增加？目标2）促炎细胞因子（例如IL-1）是否使用类似于病毒的机制增加心肌炎（即增加TLR4并减少TIM-3）？ AIM 3）心肌炎发育是否需要主动病毒感染？佐剂是否使用与病毒相同的机制增加炎症？与公共卫生有关：心脏病是美国死亡的主要原因。该建议将检查先天免疫期间病毒感染对心脏病发展的辅助作用。