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.

项目概要最近由细菌病原体百日咳博德特氏菌引起的百日咳水平达到最高水平自20世纪50年代以来在美国。在典型的百日咳疾病中，呼吸道症状之后会出现以下症状：剧烈且持续的阵发性咳嗽。在婴儿中，该疾病可能发展为严重的肺部疾病并发症（通常需要医院重症监护）和致命结果是可能的。然而，我们仍然对百日咳的发病机制了解甚少，且尚无一致有效的治疗方法对患有这种潜在致命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一些相似之处反映了年龄感染的相关结果，例如婴儿中出现的白细胞增多和器官病变，但未见成年小鼠。幼年小鼠遭受致命的传播感染，而成年小鼠则将感染限制在呼吸道并恢复。婴儿与成人相对易感性的一个可能影响因素严重百日咳（以及各种其他感染）的关键在于婴儿不同且正在发育的免疫系统与成人相比。这包括有限的 Th1 极化细胞因子反应，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 的主要早期产生者）未能限制百日咳博德特氏菌感染呼吸道道并遭受致命的传播感染，类似于婴儿野生型小鼠中看到的感染。我们的初步数据表明，与强效小鼠相比，婴儿小鼠对百日咳博德特氏菌感染的 IFNg 反应较差。成年小鼠的 IFNg 反应、幼年小鼠肺和脾中 NK 细胞的相对缺乏以及较差的表达激活 NK 细胞产生 IFNg 的细胞因子。因此，我们假设 NK 缺陷幼年小鼠的细胞和 IFNg 水平和/或反应显着影响其对致命性的易感性传播百日咳博德特氏菌感染。为了检验这些假设，该提案的目的是 (i) 研究 NK 细胞的贡献和 IFNg 缺乏导致婴儿对致命传播性百日咳博德特氏菌感染的易感性，以及 (ii) 确定 NK 细胞激活细胞因子的产生是否存在缺陷（导致较低的婴儿中 IFNg 的产生是由于巨噬细胞对百日咳博德特氏菌的反应缺乏激活。我们将结合小鼠感染、过继细胞转移和细胞培养研究来检验这些假设并开始研究机制，我们将利用基因改造小鼠来促进这些研究。鉴定宿主靶点以开发针对患有以下疾病的婴儿的新疗法使人衰弱、有时甚至致命的百日咳将对这种疾病产生重大的公共卫生影响。