Age-dependent role of interferon lambda in protection against pertussis lethality in infants

项目摘要 最近的细菌性疾病百日咳的发病率达到了60年来的最高水平。当百日咳在 青少年和成人的特征是持续的虚弱咳嗽，婴儿百日咳可 从呼吸道症状发展为更严重和复杂的疾病。这常常需要 儿童因百日咳而住院和进入儿科重症监护室，百日咳仍然导致婴儿死亡人数惊人。然而，没有有效的治疗方法存在治疗严重百日咳，我们仍然有一个相对较差的了解这种疾病的发病机制和保护性免疫反应的性质。通过RNAseq转录组学分析，我们确定了III型干扰素（IFNλ）受体亚基IFNLR 1是B肺中基因表达的最重要上游激活因子之一。百日咳感染的成年小鼠在炎症阶段。III型IFN是免疫应答和抗病毒防御中的关键细胞因子，但它们在感染和疾病模型中对炎症和发病机制也具有不同的影响。我们发现IFNλ信号在促进B的肺部炎症病理中起重要作用。百日咳感染的成年小鼠。然而，我们已经发现，百日咳发病机制是显着不同的婴儿小鼠从成年小鼠，反映了年龄依赖性的结果感染的人。受感染的野生型幼鼠（7日龄接种）不上调IFNλ表达，并出现致命的播散性感染，伴白细胞增多和肺动脉高压，这在人类婴儿的致命性百日咳病例中也可见。在7日龄接种的婴儿IFNLR1 KO小鼠（其中IFNλ信号传导被消除）也遭受致命的百日咳感染，死亡发生在与野生型小鼠相同的时间范围内。 然而，百日咳致死率在幼龄小鼠中是年龄依赖性的，因为在10日龄接种的野生型小鼠在相同剂量的感染下存活。与此形成鲜明对比的是，80%的IFNLR1基因敲除小鼠在10日龄时接种了致命的百日咳感染。我们假设年龄依赖性IFNλ信号在保护婴儿免受严重和致命的百日咳中起重要作用，并且小于一定年龄的婴儿不能诱导这种保护性IFNλ应答。因此，本探索性建议的目的是（i）研究IFNλ信号通路对B结局的年龄依赖性影响。百日咳感染的幼鼠，和（ii）确定用纯化的IFNλ治疗是否提供针对致死性B的保护。百日咳感染的小鼠。这些研究将增加我们对年龄依赖性IFNλ生物学的理解，揭示婴儿中重要的免疫缺陷，使他们容易受到致命的百日咳感染， 确定一种潜在的新型宿主靶向治疗重症百日咳的方法，这将有助于挽救受感染婴儿的生命。

PROJECT SUMMARY Recent levels of the bacterial disease pertussis are at their highest in 60 years. While pertussis in adolescents and adults is characterized by a persistent debilitating cough, pertussis in infants can progress from respiratory symptoms to more severe and complicated disease. This often requires hospitalization and admission to a pediatric intensive care unit, and pertussis still causes an alarming number of deaths in infants. However, no effective therapies exist for treatment of severe pertussis and we still have a relatively poor understanding of the pathogenesis of this disease and the nature of protective immune responses. Through RNAseq transcriptomics analysis we identified the type III interferon (IFNλ) receptor subunit, IFNLR1, as one of the most significant upstream activators of gene expression in the lungs of B. pertussis-infected adult mice during the inflammatory phase. Type III IFNs are key cytokines in immune responses and antiviral defense, but they also have diverse effects on inflammation and pathogenesis in models of infection and disease. We found that IFNλ signaling plays an important role in promoting lung inflammatory pathology in B. pertussis-infected adult mice. However, we have found that pertussis pathogenesis is markedly different in infant mice from that in adult mice, reflecting the age-dependent outcomes of infection in humans. Infected infant wild type mice (inoculated at 7 days of age) do not upregulate IFNλ expression and suffer a fatal disseminating infection with leukocytosis and pulmonary hypertension, features also seen in fatal pertussis cases in human infants. Infant IFNLR1 KO mice (in which IFNλ signaling is abrogated) inoculated at 7 days of age also suffered fatal pertussis infection, with deaths occurring in the same timeframe as those in wild type mice. However, pertussis lethality is age-dependent in young mice, since wild type mice inoculated at 10 days of age survive infection with the same dose. In striking contrast, 80% of IFNLR1 KO mice inoculated at 10 days of age suffered fatal pertussis infection. We hypothesize that age-dependent IFNλ signaling plays an important role in protecting infants against severe and fatal pertussis, and that infants younger than a certain age fail to induce this protective IFNλ response. Therefore, the aims of this exploratory proposal are to (i) investigate age-dependent effects of the IFNλ signaling pathway on outcomes in B. pertussis-infected infant mice, and (ii) determine whether treatment with purified IFNλ provides protection against lethal B. pertussis infection in infant mice. These studies will increase our understanding of age-dependent IFNλ biology, reveal an important immune deficiency in infants that renders them susceptible to lethal pertussis infection and identify a potential novel host-targeted treatment for severe pertussis that will help save the lives of infected infants.