Active Subversion of Innate Immunity by Bacterial LysM Protein

细菌 LysM 蛋白主动颠覆先天免疫

• 批准号: 8887925
• 负责人: Laurel L Lenz
• 金额: $ 45.07万
• 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: 2014-07-10 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887925
• 关键词: Activated Natural Killer Cell; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Bacteria; Bacterial Infections; Bacterial Proteins; Binding; Biological; Carbohydrates; Categories; Cause of Death; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Cultured Cells; Data; Dendritic Cells; Diagnosis; Disease; Food; Glycoproteins; Health; Host resistance; Human; Immune; Immune response; Immune system; Immunity; Infection; Integration Host Factors; Interferon Type I; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Interleukin-18; Lead; Ligands; Listeria monocytogenes; Macrophage Activation; Maps; Mediating; Modeling; Mus; Mycoplasma; N-terminal; NK Cell Activation; National Institute of Allergy and Infectious Disease; Natural Immunity; Natural Killer Cells; Pathogenesis; Pathogenicity; Patients; Peptides; Population; Predisposition; Production; Protein Region; Proteins; Publishing; Reporting; Streptococcus pneumoniae; Systemic infection; Testing; Virulence Factors; Virus Diseases; Work; adaptive immunity; base; macrophage; molecular imaging; mortality; mouse model; mutant; novel; pathogen; pathogenic bacteria; polypeptide; prevent; protective effect; receptor; respiratory; response; secretion process; targeted treatment; tumor

DESCRIPTION (provided by applicant): Intracellular pathogens cause a staggering number of human infections and deaths. The ability to subvert host innate immune responses is a key factor in the establishment of infections by these pathogens. Listeria monocytogenes is a facultative intracellular bacterial pathogen of humans and animals and is frequently used as a model to dissect mechanisms of immunity and pathogenesis. Our prior studies with L. monocytogenes identified a bacterial protein, p60, whose expression and secretion from the bacterium is required for pathogenicity in the mouse model of systemic infection. p60 is not required for Lm infection in cultured cells. We found that p60 stimulates the activation of host natural killer (NK) cells, an immune cell population associated with increased host susceptibility to L. monocytogenes and several other pathogenic bacteria. We have shown that p60 stimulates NK cells by binding to dendritic cells, and eliciting the production of IL-1� and IL-18. The ability of p60 to activate DCs and NK cells maps to a region of the protein containing a LysM domain. Purified p60 protein, or just the region of p60 containing the LysM domain is sufficient to stimulate NK cell activation. The host factor NLRP3 is also required for IL-18 production and NK cell activation in cultures with DCs, NK cells, and p60. In our first Aim, we will further define the mechanisms by which the LysM domain containing peptide uniquely binds and stimulates DCs for IL-18 production and NK cell activation. Molecular, imaging, immunological, and cell biological approaches will be used. In our second Aim, we will investigate how NLRP3 impacts host resistance during systemic bacterial infections. In our third Aim, we will characterize NK cells producing IL-10 in response to L. monocytogenes infection and p60. We also test how IL-10 production by NK cells impacts host immune responses and susceptibility to bacterial infection. Together, our work will reveal how LysM-containing bacterial virulence factors subversively activate specific aspects of innate immunity in order to promote the establishment of systemic infections.

描述（由申请人提供）：细胞内病原体导致惊人数量的人类感染和死亡。破坏宿主先天免疫应答的能力是这些病原体建立感染的关键因素。单核细胞增生李斯特菌是一种兼性细胞内细菌病原体的人类和动物，并经常被用作一个模型，剖析免疫和发病机制。我们以前的研究与L。单核细胞增多症鉴定了一种细菌蛋白p60，其从细菌中的表达和分泌是全身感染小鼠模型中致病性所需的。在培养的细胞中，Lm感染不需要p60。我们发现p60刺激宿主自然杀伤（NK）细胞的活化，NK细胞是一种与宿主对L.单核细胞增多症和其他几种致病菌。我们已经证明，p60通过与树突状细胞结合，并引发IL-1 β和IL-18的产生来刺激NK细胞。 p60激活DC和NK细胞的能力映射到含有LysM结构域的蛋白质区域。纯化的p60蛋白，或仅含有LysM结构域的p60区域足以刺激NK细胞活化。宿主因子NLRP 3也是在具有DC、NK细胞和p60的培养物中IL-18产生和NK细胞活化所需的。在我们的第一个目标中，我们将进一步确定含有LysM结构域的肽独特地结合并刺激DC产生IL-18和NK细胞活化的机制。将使用分子、成像、免疫学和细胞生物学方法。在我们的第二个目标中，我们将研究NLRP 3如何影响系统性细菌感染期间的宿主抗性。在我们的第三个目标中，我们将表征NK细胞响应于L.单核细胞增多症和p60。我们还测试了NK细胞产生的IL-10如何影响宿主免疫反应和对细菌感染的易感性。总之，我们的工作将揭示含LysM的细菌 毒力因子破坏性地激活先天免疫的特定方面，以促进系统性感染的建立。