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

干扰素 lambda 在防止婴儿百日咳致死方面的年龄依赖性作用

• 批准号: 10591086
• 负责人: NICHOLAS H CARBONETTI
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-10 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591086
• 关键词: Admission activity; Adolescent; Adult; Affect; Age; Animal Model; Bacterial Infections; Biology; Bordetella pertussis; Cessation of life; Coughing; Data; Disease; Disease Outcome; Dose; Epidemic; Gene Expression; Hospitalization; Human; Immune; Immune response; Infant; Infection; Inflammation; Inflammatory; Interferon Receptor; Interferon Type II; Interferons; Knockout Mice; Leukocytosis; Lung; Modeling; Mus; Nature; Outcome; Pathogenesis; Pathology; Pathway interactions; Pediatric Intensive Care Units; Pertussis; Phase; Play; Predisposition; Pulmonary Hypertension; Resistance; Respiratory Disease; Respiratory Signs and Symptoms; Role; Signal Pathway; Signal Transduction; Systemic disease; Testing; Therapeutic Intervention; Vaccination; Viral; Wild Type Mouse; age group; age related; cytokine; effective therapy; infant infection; mouse model; novel; pathogen; pathogenic bacteria; protective effect; receptor; response; targeted treatment; therapeutic target; transcriptome sequencing; transcriptomics

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.

项目概要 最近，百日咳细菌性疾病的发病率达到了 60 年来的最高水平。 青少年和成人的特点是持续虚弱的咳嗽，婴儿百日咳可以 从呼吸道症状发展为更严重和复杂的疾病通常需要。 住院和进入儿科重症监护室以及百日咳仍然导致婴儿死亡人数惊人。然而，目前尚无治疗重症百日咳的有效疗法，而且我们对该疾病的发病机制和性质仍知之甚少。通过 RNAseq 转录组学分析，我们确定了 III 型干扰素 (IFNλ) 受体亚基 IFNLR1 是芽孢杆菌肺部基因表达最重要的上游激活剂之一。在炎症阶段感染百日咳的成年小鼠中，III 型干扰素是免疫反应和抗病毒防御的关键细胞因子，但它们对感染和疾病模型中的炎症和发病机制也有多种影响。促进百日咳博德特氏菌感染的成年小鼠的肺部炎症病理学然而，我们发现婴儿小鼠的百日咳发病机制与成年小鼠显着不同，反映了人类感染的年龄依赖性结果。受感染的婴儿野生型小鼠（7 天龄接种）不会上调 IFNλ 表达，并会遭受致命的播散性感染，伴有白细胞增多和肺动脉高压，这些特征也见于人类婴儿致命的百日咳病例（其中 IFNLR1 KO 小鼠）。已废除）在 7 天龄时接种的小鼠也遭受了致命的百日咳感染，死亡发生时间与野生型小鼠相同。 然而，幼年小鼠的百日咳致死率具有年龄依赖性，因为在 10 天龄接种的野生型小鼠在相同剂量的感染下仍能存活。与之形成鲜明对比的是，在 10 天龄接种的 IFNLR1 KO 小鼠中，80% 遭受致命的百日咳感染。我们认为，年龄依赖性 IFNλ 信号传导在保护婴儿免受严重和致命的百日咳感染方面发挥着重要作用，并且小于一定年龄的婴儿无法诱导这种保护性 IFNλ 反应。该探索性提案的目的是 (i) 研究 IFNλ 信号通路对百日咳博德特氏菌感染的幼年小鼠结局的年龄依赖性影响，以及 (ii) 确定纯化的 IFNλ 治疗是否能提供针对致命性百日咳博德特氏菌感染的保护作用。这些研究将增进我们对年龄依赖性 IFNλ 生物学的了解，揭示婴儿体内的一种重要的免疫缺陷，该缺陷使他们容易受到致命的百日咳感染，并且 确定一种针对严重百日咳的潜在新型宿主靶向治疗方法，这将有助于挽救受感染婴儿的生命。