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

MNV-4，炎症性肠病小鼠模型中的一种新病原体

基本信息

批准号：
8471579
负责人：
LILLIAN MAGGIO-PRICE
金额：
$ 37.09万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-05 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471579
关键词：
Adoptive Transfer Animal Model Animals Antibodies Antigen Presentation Antigens Bone Marrow Calicivirus Cells Chronic Clinical Data Dendritic Cells Development Disease Disease Progression Etiology Event Exposure to Facility Designs Genetic Goals Housing Immune Immune response Immunocompetent Immunocompromised Host Immunologics In Vitro Infection Infectious Agent Inflammation Inflammatory Inflammatory Bowel Diseases Institution Interferon-alpha Interleukin-10 Interleukin-6 Investigation Knowledge Mediating Mesentery Modeling Modification Morbidity - disease rate Mus Norovirus North America Outcomes Research Pattern recognition receptor Personal Communication Phagocytosis Phenotype Play Population Production RNA Viruses Reporting Research Research Design Rodent Role Sentinel Seroprevalences Severities Specific Pathogen Frees Spleen Surveys T cell response T-Lymphocyte Techniques Testing Time Tropism United States Universities Virus Washington Wild Type Mouse animal facility cohort cytokine disease phenotype experience germ free condition human disease in vivo lymph nodes macrophage mortality mouse model pathogen receptor research facility research study response

项目摘要

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".

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。最初，该病毒似乎只在免疫功能低下的小鼠中引起发病率和死亡率，而在免疫能力强的小鼠中没有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，即使是在野生型小鼠中，该病毒还可以改变细菌诱导的炎症性肠病小鼠模型的疾病表型。MNV加重IBD的作用部分是通过对树突状细胞的作用实现的。此外，我们观察到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，我们认为MNV有可能成为啮齿动物研究中的一个主要干扰变量。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。在我们建议的研究中，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，而且我们有证据表明MNV改变了IBD的发生/进展。首先，我们将在三种常用的IBD模型中确定MNV感染是否以及如何加剧IBD。接下来，我们将确定MNV是否通过改变DC而改变抗原提呈，从而改变免疫正常和免疫缺陷小鼠对抗原的免疫反应。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。这项申请中拟议的研究将填补目前知识的空白，以确定是否应该投入时间和精力从研究设施中消除MNV。因此，我们的应用符合当前RFA的目标，即支持“小鼠诺沃克病毒感染对免疫反应的影响”的研究。