权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

NK cell and interferon gamma deficiency in infant susceptibility to pertussis

NK细胞和γ干扰素缺乏导致婴儿对百日咳的易感性

基本信息

批准号：
10369616
负责人：
NICHOLAS H CARBONETTI
金额：
$ 19.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2021-03-11 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369616
关键词：
Acute respiratory infection Address Adoptive Cell Transfers Adoptive Transfer Adult Aerosols Bacteria Bacterial Infections Bordetella pertussis Case Study Cell Culture Techniques Child Coughing Cytokine Gene Data Dendritic Cells Development Disease Epidemic Exhibits Fatal Outcome Gene Expression Hospitalization Hospitals Human IFNGR1 gene Immune Immune response Immune system Infant Infection Inflammasome Inflammatory Response Intensive Care Interferon Type II Interleukin-12 Interleukin-18 Knowledge Lead Lung Macrophage Activation Mus Natural Killer Cells Nature Organ Outcome Pathogenesis Pathology Pertussis Predisposition Production Public Health Pulmonary Hypertension Recombinant Interferon Respiratory Disease Respiratory Signs and Symptoms Respiratory System Risk Role Signal Transduction Spleen Stimulus System Systemic disease Testing Therapeutic Intervention Vaccination Wild Type Mouse Work age related care outcomes cytokine effective therapy experience in vivo infant infection interleukin-18 binding protein macrophage mouse model novel novel therapeutics pathogenic bacteria response targeted treatment therapeutic evaluation therapeutically effective treatment effect

项目摘要

PROJECT SUMMARY Recent levels of pertussis, caused by the bacterial pathogen Bordetella pertussis, are at their highest in the U.S. since the 1950s. In typical pertussis disease, respiratory symptoms are followed by episodes of severe and persistent paroxysmal coughing. In infants, the disease can progress to serious pulmonary complications, often requiring hospital intensive care, and fatal outcomes are possible. However, we still have a poor understanding of the pathogenesis of pertussis and there are no consistently effective therapeutic interventions for infants suffering from this potentially deadly bacterial infection. In mouse models of pertussis, several parallels with human pertussis disease reflect the age- dependent outcomes of infection, such as hyperleukocytosis and organ pathologies seen in infant but not adult mice. Infant mice suffer a lethal disseminating infection while adult mice restrict infection to the respiratory tract and recover. A likely contributing factor to the relative susceptibility of infants versus adults to severe pertussis (and to various other infections) is the different and developing immune system of infants compared to that of adults. This includes limited Th1-polarizing cytokine responses, primarily interferon gamma (IFNg), to most stimuli in infants. Interestingly, adult mice lacking either the IFNg receptor (IFNgR) or natural killer (NK) cells (major early producers of IFNg) fail to restrict B. pertussis infection to the respiratory tract and suffer a lethal disseminating infection, similar to the infection seen in infant wild type mice. Our preliminary data indicate poor IFNg responses to B. pertussis infection in infant mice in contrast to robust IFNg responses in adult mice, a relative deficit of NK cells in the lungs and spleens of infant mice, and poor expression of cytokines that activate NK cells to produce IFNg. Therefore, we hypothesize that deficient NK cell and IFNg levels and/or responses in infant mice contribute significantly to their susceptibility to lethal disseminating B. pertussis infection. To test these hypotheses, the aims of this proposal are (i) to investigate the contribution of NK cell and IFNg deficiencies to the susceptibility of infants to lethal disseminating B. pertussis infection, and (ii) to determine whether deficiency in production of NK cell-activating cytokines (resulting in lower IFNg production) in infants is due to deficiency in macrophage activation in response to B. pertussis. We will use a combination of mouse infection, adoptive cell transfer and cell culture studies to test these hypotheses and begin to investigate mechanisms, and we will take advantage of genetically altered mice to facilitate these studies. Identification of host targets for development of novel therapeutics for infants suffering from debilitating and sometimes fatal pertussis will have a major public health impact on this disease.

项目摘要最近由细菌病原体百日咳博德特氏菌引起的百日咳发病率达到最高水平在美国自1950年以来。在典型的百日咳疾病中，呼吸道症状之后是剧烈持续的阵发性咳嗽。在婴儿中，该疾病可进展为严重的肺部并发症，往往需要医院重症监护，和致命的结果是可能的。不过我们还是对百日咳的发病机制了解不多，对患有这种可能致命的细菌感染的婴儿进行治疗干预。在小鼠百日咳模型中，与人类百日咳疾病的几个相似之处反映了年龄- 感染的依赖性结果，如高白细胞血症和在婴儿中观察到的器官病理学，成年老鼠幼年小鼠遭受致命的传播感染，而成年小鼠将感染限制在呼吸道和恢复。一个可能的促成因素，婴儿相对于成人的相对易感性与严重百日咳（以及各种其他感染）的区别在于婴儿不同的和发育中的免疫系统与成年人相比。这包括有限的Th 1极化细胞因子应答，主要是干扰素 γ（IFNg），对婴儿的大多数刺激。有趣的是，缺乏IFNg受体（IFNgR）或自然杀伤（NK）细胞（IFNg的主要早期生产者）不能限制B。呼吸道百日咳感染感染并遭受致命的传播感染，类似于在幼年野生型小鼠中观察到的感染。我们初步数据表明对B的IFNg应答较差。百日咳感染的婴儿小鼠相比，鲁棒成年小鼠的IFNg应答，幼年小鼠的肺和脾中NK细胞的相对缺乏，表达激活NK细胞以产生IFNg的细胞因子。因此，我们假设NK细胞缺陷细胞和IFNg水平和/或应答显著影响它们对致死性传播B。百日咳感染为了验证这些假设，本研究的目的是：（i）研究NK细胞在肿瘤发生中的作用，和IFNg缺乏与婴儿对致死性传播性B的易感性有关。百日咳感染，以及（ii）确定NK细胞活化细胞因子产生的缺陷（导致较低的 IFNg产生）是由于响应于B的巨噬细胞活化不足。百日咳。我们将使用小鼠感染、过继细胞转移和细胞培养研究的组合来检验这些假设并开始研究其机制，我们将利用转基因小鼠来促进这些研究。鉴定宿主靶标以开发用于患有以下疾病的婴儿的新疗法：使人虚弱，有时甚至致命的百日咳对这种疾病的公共卫生有重大影响。