MNV-4, an Emerging Pathogen in Murine Models of Inflammatory Bowel Disease

描述（由申请方提供）：鼠诺如病毒（MNV）是小鼠中的一种潜在病原体。最初，该病毒似乎仅在免疫功能低下的小鼠中引起发病率和死亡率，而在免疫功能正常的小鼠中未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，即使在野生型小鼠中，并且该病毒改变了细菌诱导的炎症性肠病小鼠模型中的疾病表型。MNV加重IBD部分是通过对树突状细胞的影响介导的。此外，我们观察到MNV感染改变了骨髓源性巨噬细胞中几种炎性细胞因子的产生。因此，我们认为，MNV有可能成为一个主要的干扰变量在啮齿类动物的研究。不幸的是，我们没有足够的数据来确定是否应该从研究设施中消除这种病毒。对于我们提出的研究，我们将重点关注MNV对IBD小鼠研究的影响，因为我们在IBD研究方面有丰富的经验，并且我们有证据表明MNV会改变IBD的发展/进展。首先，我们将确定MNV感染是否以及如何在三种常用的IBD模型中加重IBD。接下来，我们将确定MNV是否通过改变DC改变免疫正常小鼠和免疫缺陷小鼠中的抗原呈递并因此改变对抗原的免疫应答。最后，我们将确定MNV是否通过影响DC和巨噬细胞功能来改变免疫反应。本申请中拟定的研究将填补现有知识的差距，以确定是否应投入时间和精力从研究机构中消除MNV。因此，我们的申请符合当前RFA的目的，以支持“小鼠诺如病毒感染对免疫应答的影响”的研究。

DESCRIPTION (provided by applicant): Murine norovirus (MNV) is emerging as a potential pathogen in mice. Initially, the virus appeared 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 the virus alters disease phenotypes in a mouse model of bacterially induced inflammatory bowel disease. Exacerbation of IBD by MNV was partly mediated by effects on dendritic cells. Additionally, we observed that MNV infection alters the production of several inflammatory cytokines in bone marrow derived macrophages. Thus, we suggest that MNV has potential to become a major interfering variable in research studies with rodents. Unfortunately, we do not have sufficient data to determine whether this virus should be eliminated from research facilities. For our proposed studies, we will focus on effects of MNV on mouse studies of IBD as we have significant experience with IBD research and we have evidence that MNV alters IBD development/progression. First, we will determine if and how MNV infection exacerbates IBD in three commonly used models of IBD. Next, we will determine if MNV alters antigen presentation and consequently immune responses to antigens in immunologically normal as well as immunologically deficient mice by altering DCs. Finally, we will determine if MNV alters immune responses by influencing DC and macrophage functions. Proposed studies in this application will fill the gap in current knowledge to determine whether the time and effort should be invested in elimination of MNV from the research facilities. Thus, our application is in line with the objective of current RFA to support investigation of "the impact of murine norovirus infection on immune response".