Effects of Murine norovirus infection on Mouse Models of Atherosclerosis

描述(由申请人提供)：小鼠诺如病毒(MNV)正在成为小鼠的一种潜在病原体，其在世界各地研究机构的流行引起了使用小鼠的研究人员的关注。最初，据报道，这种病毒只会在免疫功能低下的小鼠中引起发病率和死亡率，而它不会在免疫能力强的小鼠中引起任何明显疾病的临床症状。然而，我们发现MNV感染可以诱导免疫反应的细微变化，即使在野生型小鼠中，MNV感染与Ldlr-/-小鼠的主动脉窦病变大小增加有关，Ldlr-/-小鼠是研究动脉粥样硬化的常用小鼠模型。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。其他人报道说，MNV对巨噬细胞和树突状细胞都有趋向性。我们的初步研究还发现，MNV感染改变了骨髓来源的巨噬细胞中几种炎性细胞因子的产生。因此，我们假设MNV是动脉粥样硬化研究中一个潜在的并发变量，部分原因是通过影响巨噬细胞募集、细胞因子/趋化因子分布和/或动脉粥样硬化病变中的积聚。为了验证我们的假设，我们将首先确定MNV感染是否会在另一种小鼠模型ApoE-/-小鼠中加剧动脉粥样硬化。接下来，我们将研究在两种常用的小鼠模型Ldlr-/-和ApoE-/-中，早期暴露于MNV是否会改变疾病表型。最后，我们将通过检测巨噬细胞的变化来确定MNV如何改变疾病的结局。巨噬细胞是参与疾病发生和发展的重要先天免疫细胞。本申请中拟议的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，我们的应用与当前RFA的目标一致，即支持“小鼠诺沃克病毒感染对免疫反应的影响”的调查。

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".