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.

项目总结 最近，细菌性百日咳的发病率达到了60年来的最高水平。当百日咳在 青少年和成人的特点是持续虚弱的咳嗽，婴儿百日咳可 从呼吸道症状发展到更严重和更复杂的疾病。这通常需要 住院和进入儿科重症监护病房，百日咳仍然造成婴儿死亡的惊人数字。然而，目前还没有有效的治疗方法来治疗重症百日咳，我们对这种疾病的发病机制和保护性免疫反应的性质仍然知之甚少。通过RNAseq转录分析，我们确定了III型干扰素λ受体亚基IFNLR1是感染百日咳杆菌的成年小鼠在炎症阶段肺组织中最重要的基因表达上游激活因子之一。III型干扰素是免疫反应和抗病毒防御的关键细胞因子，但在感染和疾病模型中，它们在炎症和发病机制中也有不同的作用。我们发现干扰素λ信号在百日咳杆菌感染的成年小鼠的肺部炎症病理中起重要作用。然而，我们发现百日咳的发病机制在幼年小鼠和成年小鼠中有明显的不同，反映了人类感染的年龄相关性结果。感染的婴儿野生型小鼠(7日龄接种)不会上调干扰素λ的表达，并遭受致命的传播性感染，并伴有白细胞增多和肺动脉高压，这一特征也见于人类婴儿致命的百日咳病例。7日龄婴儿接种IFNLR1KO小鼠(其中干扰素λ信号被取消)也发生致命的百日咳感染，死亡时间与野生型小鼠相同。 然而，百日咳在幼鼠中的致死率与年龄有关，因为在10天大时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日龄时接种的IFNLR1KO小鼠中，有80%的小鼠出现了致命的百日咳感染。我们假设依赖年龄的干扰素λ信号在保护婴儿免受严重和致命性百日咳的侵袭中发挥重要作用，而小于一定年龄的婴儿不能诱导这种保护性的干扰素λ反应。因此，这项探索性建议的目的是(I)研究干扰素λ信号通路对感染百日咳杆菌的幼鼠结局的年龄依赖性影响，以及(Ii)确定纯化的干扰素λ治疗是否对幼年小鼠致死性百日咳杆菌感染具有保护作用。这些研究将增加我们对年龄依赖性干扰素λ生物学的理解，揭示婴儿的一种重要的免疫缺陷，使他们容易受到致命性百日咳感染和 确定一种潜在的针对严重百日咳的宿主靶向治疗方法，这将有助于挽救受感染婴儿的生命。