Understanding IL-27 as a negative regulator of protective immunity during neonatal sepsis

了解 IL-27 作为新生儿败血症期间保护性免疫的负调节因子

基本信息

批准号：
10278311
负责人：
Cory Michael Robinson
金额：
$ 50.96万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10278311
关键词：
Address Adult Annual Reports Anti-Inflammatory Agents Antibiotic Resistance Antibiotics Antibodies Bacteremia Bacteria Bacterial Infections Biological Assay Cells Cessation of life Child Communicable Diseases Coupled Data Disease Escherichia coli Exhibits Frequencies Goals Growth Human IL27RA gene Immune Immune Targeting Immune response Immune system Immunity Immunologics Immunotherapeutic agent Impairment In Vitro Infant Mortality Infection Inflammation Inflammatory Response Interleukins Knockout Mice Knowledge Laboratories Life Low Birth Weight Infant Lung Measures Mediating Modeling Molecular Morbidity - disease rate Mus Newborn Infant Outcome Pathology Pathway interactions Penetration Peripheral Phagocytes Phenotype Population Predisposition Production Proteins Publishing Reporter Research Risk Risk Factors Sepsis Serum Shapes Signal Pathway Signal Transduction Site Source Stat3 Signaling Pathway Stat3 protein Supportive care Therapeutic Intervention Time Tissues Transcript Transgenic Mice Translating Ursidae Family Validation Visualization Vulnerable Populations Weight Gain Work antibody conjugate burden of illness cell type combat cytokine early detection biomarkers early onset high risk imaging approach immunological intervention improved in vivo macrophage microbial monocyte mortality mortality risk mouse model neonatal mice neonatal period neonatal sepsis neonate neutralizing antibody neutrophil pathogenic bacteria potential biomarker pre-clinical promoter prophylactic pup receptor binding single-cell RNA sequencing targeted treatment trafficking whole animal imaging

项目摘要

PROJECT SUMMARY Microbial infections are a major cause of infant mortality worldwide. For particularly vulnerable populations such as pre-term and low birthweight babies, the risk of invasive infections further escalates. The neonatal period is defined by a distinct, often described as immature, immune system. Many features of a protective host response to infection are deficient as compared with older children and adults. Our laboratory has identified that expression of the immune suppressive cytokine interleukin (IL)-27 is elevated in human and murine neonates. Other recent studies have shown IL-27 to be a biomarker for early onset neonatal sepsis. This suggests that elevated IL-27 may represent a risk factor and when further increased during bacterial challenge, compromise the host immune response. The overall premise of the current proposal is that IL-27 is a host molecule that represents a target for immune intervention to improve the host response and reduce susceptibility to bacterial infection early in life. We present strong evidence in a mouse model that the absence of IL-27 signaling translates to increased survival, improved weight gain, and enhanced clearance of bacteria during neonatal sepsis. To advance our knowledge of how IL-27 regulates the immune response during neonatal sepsis, we need to identify the complete repertoire of cell types responsible for IL-27 production, understand how these population may change over the course of infection, and further define their functionality. We will address this gap in understanding using an IL-27 reporter mouse that expresses a fluorescent protein under control of the IL-27p28 promoter. Using whole-animal imaging of the reporter mouse coupled with luminescent bacteria, this will allow us to identify IL-27 producers, sort them for further functional analysis, and correlate their presence in infected tissues with the bacterial burden. We also seek to understand cellular signaling pathways required for IL-27-mediated suppressive activity and compromised control of the bacterial burden. We hypothesize that signal transducer and activator of transcription (Stat)-3 signals downstream of IL-27 receptor binding to interfere with lysosomal trafficking and acidification. The net result is compromised bacterial clearance. Lastly, a primary objective is to investigate the outcomes of antagonizing IL- 27 during neonatal sepsis with the aim of establishing an immunotherapeutic approach for an infectious disease for which we can currently only offer antibiotics and supportive care. Antibiotic resistance confounds our reliance on this approach. Administration of a neutralizing antibody conjugated to a fluorescent tag will allow for visualization of tissue penetration in real time and directly correlate the presence of the antagonist with control of bacterial growth. At the completion of this project, we expect to have performed preclinical validation of a promising immunotherapeutic approach to improve immunological responses and susceptibility to infection disease in newborns, as well as provided an enhanced understanding of how IL-27 regulates host immunity and interactions with bacterial pathogens during neonatal sepsis.

项目概要微生物感染是全世界婴儿死亡的主要原因。对于特别脆弱的人群例如早产儿和低出生体重儿，侵袭性感染的风险进一步上升。新生儿时期是由独特的、通常被描述为不成熟的免疫系统定义的。保护器的许多功能与年龄较大的儿童和成人相比，宿主对感染的反应不足。我们实验室有发现免疫抑制细胞因子白细胞介素 (IL)-27 的表达在人类和小鼠新生儿。最近的其他研究表明 IL-27 是早发新生儿败血症的生物标志物。这表明 IL-27 升高可能是一个危险因素，当细菌感染期间进一步升高时，IL-27 可能会升高。挑战，损害宿主免疫反应。当前提案的总体前提是 IL-27 是代表免疫干预目标的宿主分子，以改善宿主反应并减少生命早期易受细菌感染。我们在小鼠模型中提供了强有力的证据表明缺乏 IL-27 信号转导可提高存活率、改善体重并增强细菌清除率新生儿败血症期间。加深我们对 IL-27 如何调节免疫反应的了解新生儿败血症，我们需要确定负责产生 IL-27 的完整细胞类型，了解这些人群在感染过程中可能发生的变化，并进一步定义他们的功能。我们将使用 IL-27 报告小鼠来解决这一理解上的差距，该小鼠表达 IL-27p28 启动子控制下的荧光蛋白。使用报告小鼠的全动物成像与发光细菌相结合，这将使我们能够识别 IL-27 生产者，对它们进行分类以获得进一步的功能分析，并将它们在受感染组织中的存在与细菌负荷相关联。我们也试图了解 IL-27 介导的抑制活性和受损控制所需的细胞信号通路细菌负担。我们假设信号转导子和转录激活子 (Stat)-3 发出信号 IL-27 受体结合的下游干扰溶酶体运输和酸化。最终结果是细菌清除受损。最后，主要目标是研究拮抗IL-的结果 27 在新生儿败血症期间，旨在建立针对感染性疾病的免疫治疗方法目前我们只能提供抗生素和支持性护理的疾病。抗生素耐药性令人困惑我们对这种方法的依赖。施用与荧光标签缀合的中和抗体将允许实时观察组织渗透并直接关联拮抗剂的存在并控制细菌生长。在该项目完成时，我们预计已经进行了临床前研究验证一种有前途的免疫治疗方法，以改善免疫反应和易感性新生儿感染性疾病，并加深了对 IL-27 如何调节宿主的了解新生儿败血症期间的免疫和与细菌病原体的相互作用。