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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：
8310152
负责人：
LILLIAN MAGGIO-PRICE
金额：
$ 39万
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/8310152
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）：鼠诺如病毒（MNV）正在成为小鼠的潜在病原体。最初，该病毒似乎仅在免疫功能低下的小鼠中引起发病和死亡，而不会在免疫功能正常的小鼠中引起任何明显疾病的临床症状。然而，我们发现，即使在野生型小鼠中，MNV 感染也能引起免疫反应的微妙变化，并且该病毒会改变细菌诱导的炎症性肠病小鼠模型中的疾病表型。 MNV 导致 IBD 恶化的部分原因是对树突状细胞的影响。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症细胞因子的产生。因此，我们认为 MNV 有可能成为啮齿类动物研究中的主要干扰变量。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。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 研究方面拥有丰富的经验，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 模型中加剧 IBD。接下来，我们将确定 MNV 是否通过改变 DC 来改变免疫正常和免疫缺陷小鼠中的抗原呈递，从而改变对抗原的免疫反应。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。本申请中提出的研究将填补当前知识的空白，以确定是否应投入时间和精力来消除研究设施中的 MNV。因此，我们的申请符合当前 RFA 的目标，即支持“鼠诺如病毒感染对免疫反应的影响”的研究。