Genetic predisposition and anti-IFN autoantibodies underlying severe influenza.

严重流感的遗传易感性和抗干扰素自身抗体。

• 批准号: 505474100
• 负责人: Professor Dr. Martin Schwemmle
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Hygiene (IMMH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505474100?language=en
• 关键词: Genetic; predisposition; anti; IFN; autoantibodies

Life-threatening influenza pneumonia is a major public health problem, by its number, and a long-standing scientific enigma, because most cases of influenza are benign. Clinical manifestations and outcome of Influenza A virus (IAV) infections may possibly be determined by both viral and host factors. While life-threatening influenza pneumonia can be favored by co-morbidities, most cases in otherwise healthy individuals remain unexplained. The French team previously identified single-gene inborn errors of type I and III interferon (IFN) immunity as genetic etiologies of life-threatening influenza pneumonia, including autosomal recessive (AR) IRF7, AR IRF9, and autosomal dominant (AD) TLR3 deficiencies. The German team discovered that rare, deleterious variants of the IFN-stimulated gene (ISG) MX1 increase susceptibility to zoonotic infections with the avian IAV subtype H7N9. On this evidently complementary basis, the two teams now hypothesize that these and other genetic determinants of innate immunity may underlie critical influenza in many more patients than hitherto suspected. In a highly synergistic effort, we will analyze whole exomes of a large, diverse cohort of more than 300 patients with severe influenza, searching for inborn errors of immunity (IEI), with a particular - but not exclusive - interest in type I and III IFN IEI recently found to underlie critical COVID-19 pneumonia. We will also test the candidate rare variants at the molecular, cellular, and immunological levels. Finally, we will search for autoantibodies (auto-Abs) neutralizing type I and III IFNs that were recently shown to account for about 20% of COVID-19 deaths and to reach 4% of individuals older than 70 years old in the general population. Our preliminary data are exciting. We have recruited pediatric and adult patients with life-threatening IAV infections, in collaboration with multiple international partners. We have also found three new candidate genetic disorders, including X-linked recessive (XR) TLR8, AR NLRC3, and AR MX2 deficiencies. Finally, we have identified auto-Abs neutralizing IFN-alpha and/or -omega in 10-20% of a small cohort of patients with severe influenza. The biological and clinical implications of our study are multiple and important. Biologically, we will provide additional evidence that life-threatening influenza pneumonia can be driven by human genetic and immunological determinants that undermine type I and III IFN immunity to IAV in the respiratory tract. Clinically, we will provide a rationale not only for annual influenza vaccination of individuals at risk, but also for specific therapeutic options in patients with deficiencies in type I and III IFN immunity due to genetic disorders or anti-IFN auto-Abs.

就其数量而言，危及生命的流感肺炎是一个重大的公共卫生问题，也是一个长期存在的科学谜团，因为大多数流感病例都是良性的。甲型流感病毒 (IAV) 感染的临床表现和结果可能由病毒和宿主因素共同决定。虽然合并症可能会导致危及生命的流感肺炎，但在其他方面健康的个体中，大多数病例仍无法解释。法国研究小组此前将I型和III型干扰素（IFN）免疫的单基因先天性缺陷确定为危及生命的流感肺炎的遗传病因，包括常染色体隐性（AR）IRF7、AR IRF9和常染色体显性（AD）TLR3缺陷。德国研究小组发现，干扰素刺激基因 (ISG) MX1 的罕见有害变异会增加对禽类 IAV H7N9 亚型人畜共患感染的易感性。在这个明显互补的基础上，两个团队现在假设，先天免疫的这些和其他遗传决定因素可能是导致危重流感的原因，其患者数量可能比迄今为止所怀疑的要多。在高度协同的努力中，我们将分析由 300 多名严重流感患者组成的大型、多样化队列的整个外显子组，寻找先天性免疫错误 (IEI)，特别是（但并非排他性）I 型和 III 型最近发现 IFN IEI 是严重的 COVID-19 肺炎的基础。我们还将在分子、细胞和免疫学水平上测试候选的罕见变异。最后，我们将寻找中和 I 型和 III 型干扰素的自身抗体 (auto-Abs)，最近发现这些抗体约占 COVID-19 死亡的 20%，并影响到普通人群中 70 岁以上老年人的 4%。我们的初步数据令人兴奋。我们与多个国际合作伙伴合作，招募了患有危及生命的 IAV 感染的儿童和成人患者。我们还发现了三种新的候选遗传性疾病，包括 X 连锁隐性 (XR) TLR8、AR NLRC3 和 AR MX2 缺陷。最后，我们在一小群严重流感患者中发现了中和 IFN-α 和/或 omega 的自身抗体，其中有 10-20%。我们的研究具有多重且重要的生物学和临床意义。从生物学角度来看，我们将提供更多证据，证明危及生命的流感肺炎可能是由人类遗传和免疫决定因素引起的，这些决定因素会破坏呼吸道中对 IAV 的 I 型和 III 型 IFN 免疫力。在临床上，我们不仅将为高危个体每年接种流感疫苗提供依据，而且为因遗传性疾病或抗 IFN 自身抗体而导致 I 型和 III 型 IFN 免疫缺陷的患者提供具体的治疗选择。