NK cell and interferon gamma deficiency in infant susceptibility to pertussis

项目总结 最近由细菌病原体百日咳杆菌引起的百日咳病例处于最高水平。 自20世纪50年代以来在美国。在典型的百日咳病中，呼吸道症状之后会出现 严重且持续的阵发性咳嗽。在婴儿中，这种疾病可以发展为严重的肺部疾病。 可能会出现并发症，通常需要医院重症监护，并可能导致致命后果。然而，我们仍然 对百日咳的发病机制认识不深，没有一贯有效的治疗方法 对患有这种潜在致命细菌感染的婴儿进行治疗干预。 在百日咳小鼠模型中，与人类百日咳疾病的几个相似之处反映了年龄- 感染的依赖结局，如高白细胞症和婴儿的器官病理，但不是 成年小鼠。幼鼠遭受致命的传播性感染，而成年鼠将感染限制在 呼吸道和康复。婴儿与成人相对易感性的一个可能的因素 严重百日咳(和各种其他感染)是婴儿不同和发育中的免疫系统。 与成年人相比。这包括有限的Th1极化细胞因子反应，主要是干扰素 伽玛(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)未能限制百日咳杆菌对呼吸道的感染 并遭受致命的传播性感染，类似于在幼年野生型小鼠中看到的感染。我们的 初步数据显示，幼鼠对百日咳杆菌感染的IFNG反应较差，而不是健壮的 成年小鼠的IFNG反应，幼年小鼠肺和脾中NK细胞的相对缺陷，以及 激活NK细胞产生干扰素的细胞因子的表达。因此，我们假设缺乏NK细胞 幼鼠体内细胞和IFNG水平和/或反应显著影响它们对致死性的易感性 传播百日咳杆菌感染。 为了验证这些假说，这项提议的目的是(I)研究NK细胞的贡献 如果婴儿对致命性传播百日咳杆菌感染的易感性存在缺陷，以及(Ii) 确定NK细胞激活细胞因子的产生是否不足(导致较低 婴儿的免疫缺陷(IFNG产生)是由于对百日咳杆菌的巨噬细胞激活不足所致。我们会 使用小鼠感染、过继细胞转移和细胞培养研究相结合的方法来验证这些假设 并开始研究机制，我们将利用转基因小鼠来促进 这些研究。寻找宿主靶点用于开发治疗婴幼儿高血压病的新疗法 百日咳使人虚弱，有时甚至致命，这将对这种疾病的公共卫生产生重大影响。

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.