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.

危及生命的流感肺炎是其数量的主要公共卫生问题，也是长期以来的科学谜团，因为大多数流感病例都是良性的。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确定。尽管危及生命的流感肺炎可以受到合并症的青睐，但健康个体中的大多数病例仍然无法解释。法国团队先前鉴定出I型和III型干扰素（IFN）免疫的单一天生错误是威胁生命的流感肺炎的遗传病因，包括常染色体隐性膜片（AR）IRF7，AR IRF9和常染色体质体占主导地位（AD）TLR3不足。德国团队发现，IFN刺激的基因（ISG）MX1的罕见，有害的变体增加了使用鸟类IAV亚型H7N9对人畜共动性感染的敏感性。现在，在这种互补的基础上，两个团队现在假设这些先天免疫的遗传决定因素可能是许多患者的关键流感基础，而不是迄今为止怀疑。在高度协同的努力中，我们将分析300多名患有严重流感的患者的大型，多样的队列的整个外来，寻找先天性的免疫力（IEI），具有特定的 - 但不是独家 - 对I型和III类IIEI的兴趣，最近发现了IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFN IFNE IFNE IFNE IFNE IFNIFE CRIDELIE CRIDELIE CORVID COVID -COVID -COVID -COVID -19。我们还将在分子，细胞和免疫学水平上测试候选稀有变体。最后，我们将搜索中和自身抗体（自动抗体）中和I型和III型IFN，这些I型和III型IFN最近被证明占COVID-119死亡的20％，并达到普通人群中70岁以上的4％的人。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威胁生命IAV感染的儿科和成年患者。我们还发现了三个新的候选遗传疾病，包括X连锁隐性（XR）TLR8，AR NLRC3和AR MX2缺陷。最后，我们已经确定了在10-20％患有严重流感的患者中，在10-20％的患者中，自动ABS中和IFN-Alpha和/或-OMEGA。我们研究的生物学和临床意义是多重和重要的。从生物学上讲，我们将提供其他证据表明，威胁生命的流感肺炎可以由人类遗传和免疫学决定因素驱动，这些决定因素破坏了I型和III型呼吸道中IAV的免疫力。从临床上讲，我们将不仅为处于危险中的个体的年度流感疫苗接种，而且还将为I型和III型缺陷型因遗传疾病或抗IFN Auto-ABS造成的特定治疗选择提供理由。