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.

威胁生命的流感肺炎是一个重大的公共卫生问题，就其数量而言，也是一个长期存在的科学之谜，因为大多数流感病例是良性的。甲型流感病毒（IAV）感染的临床表现和结局可能由病毒和宿主因素共同决定。虽然危及生命的流感肺炎可能受到合并症的青睐，但其他健康个体的大多数病例仍然无法解释。法国研究小组先前确定I型和III型干扰素（IFN）免疫的单基因先天性缺陷是危及生命的流感肺炎的遗传病因，包括常染色体隐性（AR）IRF 7，AR IRF 9和常染色体显性（AD）TLR 3缺陷。德国研究小组发现，IFN刺激基因（ISG）MX 1的罕见有害变体增加了对禽IAV亚型H7N9人畜共患感染的易感性。在这个明显互补的基础上，两个研究小组现在假设，这些和其他先天免疫的遗传决定因素可能是比迄今为止怀疑的更多患者的关键流感的基础。在高度协同的努力中，我们将分析300多名严重流感患者的大型多样化队列的整个外显子组，寻找先天性免疫缺陷（IEI），特别是-但不是唯一的-最近发现的I型和III型IFN IEI是关键的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体。最后，我们将寻找中和I型和III型干扰素的自身抗体（自身抗体），这些抗体最近被证明占COVID-19死亡人数的约20%，并在一般人群中达到70岁以上个体的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疾病，包括X连锁隐性（XR）TLR 8，AR NLRC 3和AR MX2缺陷。最后，我们已经在10-20%的患有严重流感的小队列患者中鉴定了中和IFN-α和/或IFN-ω的自身抗体。我们的研究的生物学和临床意义是多重的和重要的。在生物学上，我们将提供更多的证据表明，危及生命的流感肺炎可以由人类遗传和免疫决定因素驱动，这些决定因素破坏了呼吸道中I型和III型IFN对IAV的免疫力。在临床上，我们将提供一个理由，不仅每年流感疫苗接种的个人的风险，但也为特定的治疗方案，在I型和III型IFN免疫缺陷的患者由于遗传疾病或抗IFN自身抗体。