Genetic predisposition and anti-IFN autoantibodies underlying severe influenza. – GENFLU

Life-threatening influenza pneumonia is a major public health problem, by its number, and a longstanding 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 lifethreatening 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.