Effects of Murine norovirus infection on Mouse Models of Atherosclerosis

鼠诺如病毒感染对小鼠动脉粥样硬化模型的影响

• 批准号: 8306671
• 负责人: LILLIAN MAGGIO-PRICE
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306671
• 关键词: Affect; Apolipoprotein E; Arterial Fatty Streak; Asia; Atherosclerosis; Blood Circulation; Bone Marrow; Cell Culture Techniques; Cells; Cholesterol; Clinical; Dendritic Cells; Development; Diet; Disease; Disease Outcome; Equilibrium; Europe; Fatty acid glycerol esters; Foam Cells; Immune; Immune response; Immunocompetent; Immunocompromised Host; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-6; Investigation; Knockout Mice; Lesion; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Mediating; Modeling; Morbidity - disease rate; Mus; Necrosis; Norovirus; Phenotype; Play; Prevalence; Production; Reporting; Research; Research Personnel; Role; Severities; Specific Pathogen Frees; Testing; Time; Tropism; United States; Valsalva sinus; Virus; Wild Type Mouse; animal facility; base; chemokine; cytokine; disease phenotype; feeding; germ free condition; macrophage; monocyte; mortality; mouse model; pathogen; research facility; response

DESCRIPTION (provided by applicant): Murine norovirus (MNV) is emerging as a potential pathogen in mice and its prevalence in research facilities around the world is causing concern among investigators using mice. Initially, the virus was reported to cause morbidity and mortality only in immunocompromised mice while it did not cause any clinical signs of overt diseases in immunocompetent mice. However, we found that MNV infection can induce subtle changes in immune responses even in wild type mice and that MNV infection was associated with an increase in aortic sinus lesion size in Ldlr-/- mice, a commonly used mouse model for atherosclerosis research. We observed that larger aortic sinus lesions in MNV infected mice were associated with increased numbers of macrophages. Others have reported that MNV has a tropism toward macrophages as well as dendritic cells. Our preliminary studies have also found that MNV infection alters the production of several inflammatory cytokines in bone marrow derived macrophages. Thus, we hypothesize that MNV is a potential intercurrent variable in atherosclerosis research partly by influencing macrophage recruitment, cytokine/chemokine profile, and or accumulation in atherosclerotic lesions. To test our hypothesis, we will first determine whether MNV infection exacerbates atherosclerosis in an additional mouse model, ApoE-/- mice. Next, we will investigate whether early exposure (before onset of atherosclerosis) to MNV alters disease phenotype in two commonly used mouse models, Ldlr-/- and ApoE-/-. Finally we will determine how MNV might alter the disease outcome by examining changes in macrophages, important innate immune cells involved in disease initiation and progression. Proposed studies in this application will provide information that can be used to determine whether time and effort should be invested in elimination of MNV from mouse research facilities. Thus, our application is in line with the objective of the current RFA to support investigation of "the impact of murine norovirus infection on immune responses".

描述（由申请方提供）：鼠诺如病毒（MNV）正在成为小鼠中的潜在病原体，其在世界各地研究机构的流行引起了使用小鼠的研究者的担忧。最初，据报道该病毒仅在免疫功能低下的小鼠中引起发病和死亡，而在免疫功能正常的小鼠中不引起任何明显疾病的临床体征。然而，我们发现，MNV感染可以诱导免疫反应的微妙变化，即使在野生型小鼠和MNV感染与Ldlr-/-小鼠，动脉粥样硬化研究中常用的小鼠模型的主动脉窦病变大小的增加。我们观察到，在MNV感染的小鼠中，较大的主动脉窦病变与巨噬细胞数量的增加有关。其他人已经报道MNV具有对巨噬细胞以及树突状细胞的向性。我们的初步研究还发现，MNV感染会改变骨髓源性巨噬细胞中多种炎症细胞因子的产生。因此，我们假设MNV是动脉粥样硬化研究中的一个潜在的并发变量，部分通过影响巨噬细胞募集，细胞因子/趋化因子谱和/或动脉粥样硬化病变中的积累。为了验证我们的假设，我们将首先确定MNV感染是否会加重另一种小鼠模型ApoE-/-小鼠的动脉粥样硬化。接下来，我们将在两种常用的小鼠模型Ldlr-/-和ApoE-/-中研究早期暴露于MNV（动脉粥样硬化发作前）是否会改变疾病表型。最后，我们将通过检查巨噬细胞的变化来确定MNV如何改变疾病的结果，巨噬细胞是参与疾病发生和发展的重要先天免疫细胞。本申请中的拟议研究将提供可用于确定是否应投入时间和精力从小鼠研究设施中消除MNV的信息。因此，我们的申请符合当前RFA的目标，以支持“小鼠诺如病毒感染对免疫应答的影响”的研究。