Natural killer cell-derived IL-10 and immunity to Listeria

自然杀伤细胞衍生的 IL-10 和对李斯特菌的免疫力

• 批准号: 8783266
• 负责人: Sarah E Clark
• 金额: $ 5.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783266
• 关键词: Affect; Bacteria; Bacterial Infections; CD8B1 gene; Cells; Coculture Techniques; Cytolysis; Data; Dendritic Cells; Development; Disease; Encephalitis; Feedback; Gastroenteritis; Goals; Host resistance; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; In Vitro; Incidence; Infection; Interferons; Interleukin-10; Interleukin-18; Knowledge; Listeria; Listeria monocytogenes; Listeriosis; Measures; Mediating; Microbe; Modeling; Mus; Myeloid Cells; NK Cell Activation; Natural Killer Cells; Parasitic infection; Phagocytes; Population; Predisposition; Production; Proteins; Regulation; Role; Sepsis; System; T-Lymphocyte; Transcript; Translations; Virus Diseases; Work; base; cell type; cytotoxicity; design; foodborne; foodborne pathogen; improved; in vivo; microorganism; neoplastic cell; pathogen; public health relevance; research study; response; therapy design; therapy development; uptake

DESCRIPTION (provided by applicant): The bacterium Listeria monocytogenes (Lm) is one of the most deadly foodborne pathogens, and is particularly dangerous in the immune compromised. How Listeria causes disease and why there is increased susceptibility in some populations remains poorly understood. During infection, Listeria and other microbes can initiate host responses that suppress, rather than contribute to, protective immunity. Identifying how microbes inhibit host immunity is integral to our understanding of host-pathogen interactions and the design of therapies to treat infection. Preliminary data suggest that Lm induces a natural killer (NK) cell-dependent, systemic IL-10 response that limits bacterial clearance. The goals of this proposal are to investigate the induction of NK cell IL-10 production and determine how NK cell-dependent IL-10 limits protective immunity to Lm. First, the stimulation of NK cell-dependent IL-10 in the context of Lm infection will be explored. The effect of IL-18, which contributes to early NK cell IFN-? production, on NK cell-dependent IL-10 expression will be determined using a co-culture system (with purified NK cells and IL-10-/- dendritic cells) in conjunction with in vio infections in mice that are unresponsive to IL-18. It is also possible that early NK cell IFN-? affects subsequent IL-10 production. The potential for feedback regulation between NK cell-dependent IFN-? and IL-10 will be investigated by transferring NK cells from mice that are unresponsive to either IFN-? or IL-10 into Lm-infected hosts. In the second half of the proposed work, the impact of NK cell-dependent IL-10 on protective immunity will be investigated. Mice with immune cell subsets that are unresponsive to IL-10 will be infected with Lm to determine the cell types required for IL-10-mediated susceptibility. Finally, the impact of NK cell-dependent IL-10 on immune cell protective activity will be evaluated in vivo by measuring CD8+ T cell cytotoxicity during Lm infection in wild-type versus IL-10-/- mice. Collectively, these experiments will explore the requirements for Lm-induced NK cell IL-10 production and establish how this response impacts host protective immunity. This work will expand our knowledge about how microbes can suppress host immunity during infection, which has broad implications for a number of diseases in which the immune response is inappropriately activated.

描述（由申请人提供）：单核细胞增生李斯特氏菌（Lm）是最致命的食源性病原体之一，对于免疫受损的人尤其危险。李斯特菌如何引起疾病以及为什么某些人群的易感性增加仍然知之甚少。在感染过程中，李斯特菌和其他微生物可以引发宿主反应，抑制而不是促进保护性免疫。确定微生物如何抑制宿主免疫对于我们理解宿主与病原体的相互作用以及治疗感染的疗法的设计至关重要。初步数据表明，Lm 会诱导自然杀伤 (NK) 细胞依赖性全身性 IL-10 反应，从而限制细菌清除。该提案的目标是研究 NK 细胞 IL-10 产生的诱导，并确定 NK 细胞依赖性 IL-10 如何限制对 Lm 的保护性免疫。首先，将探讨 Lm 感染背景下 NK 细胞依赖性 IL-10 的刺激。 IL-18 的作用有助于早期 NK 细胞 IFN-？将使用共培养系统（具有纯化的 NK 细胞和 IL-10-/- 树突状细胞）结合对 IL-18 无反应的小鼠体内感染来确定 NK 细胞依赖性 IL-10 表达的产量。也有可能早期 NK 细胞 IFN-α影响后续 IL-10 的产生。 NK 细胞依赖性 IFN- 之间的反馈调节潜力？将通过从对 IFN-α 没有反应的小鼠中转移 NK 细胞来研究 IL-10 和 IL-10。或IL-10进入Lm感染的宿主。在拟议工作的后半部分，将研究 NK 细胞依赖性 IL-10 对保护性免疫的影响。具有对 IL-10 无反应的免疫细胞亚群的小鼠将被 Lm 感染，以确定 IL-10 介导的易感性所需的细胞类型。最后，NK细胞依赖性的影响 通过测量野生型与 IL-10-/- 小鼠在 Lm 感染期间的 CD8+ T 细胞的细胞毒性，可在体内评估 IL-10 对免疫细胞保护活性。总的来说，这些实验 将探索 Lm 诱导 NK 细胞产生 IL-10 的要求，并确定这种反应如何影响宿主的保护性免疫。这项工作将扩大我们对微生物如何在感染过程中抑制宿主免疫的了解，这对免疫反应被不适当地激活的许多疾病具有广泛的影响。