Recent evidence suggests that some cases of severe viral disease arise from an imbalance in IFN-I-mediated defense. The mechanisms underlying IFN-I deficiency are mainly twofold: first, inborn errors of immunity (IEI) disrupt the production or response pathways of IFN-I; second, autoantibodies that neutralize IFN-I, such as anti-IFN-I autoantibodies, directly bind and block secreted IFN-I, as shown in the figure.
Based on this core hypothesis, we aim to establish a Taiwanese cohort for the study of severe viral disease and, by integrating clinical manifestations and immune phenotypes, systematically elucidate the molecular and genetic mechanisms that lead to severe illness.
Research Directions
I. Establishing an ISRE reporter assay to screen for neutralizing anti-IFN-I autoantibodies
A growing body of evidence has shown that neutralizing anti-IFN-I autoantibodies, including those against IFN-α, IFN-ω, and IFN-β, are associated with severe outcomes in a variety of viral infections. In Taiwanese patients with severe viral disease, we have established an ISRE (interferon-stimulated response element) reporter assay to detect whether neutralizing IFN-I autoantibodies are present in a more specific manner. This approach not only determines the presence of antibodies, but also directly evaluates their functional ability to block IFN-I signaling. Such antibodies have already been identified in patients with severe COVID-19, enterovirus 71 (EV71) infection, and severe adenovirus B7 infection. In the future, we will extend this work to more severe viral infection cohorts to clarify its clinical significance.
II. Using sequencing and next-generation sequencing to identify pathogenic inborn errors of immunity
Inborn errors of immunity (IEI) represent another key mechanism leading to IFN-I deficiency. Taking Toll-like receptor 3 (TLR3) as an example, this receptor is responsible for sensing viral nucleic acids and inducing IFN-I production. Our previous study has demonstrated that severe enteroviral encephalitis can result from TLR3 deficiency (Kuo et al., J Clin Immunol, 2022). In addition, in patients with chronic mucocutaneous candidiasis (CMC), we identified abnormalities in STAT1 and Th17-related pathway genes (Lei et al., J Clin Immunol, 2024). These findings support the concept that specific gene defects lead to susceptibility to specific pathogens. As shown in the figure, IFN-I production and signaling involve a series of molecules, including TLR3/7, MAVS, STING, TBK1, IRF3/IRF7, and the downstream IFNAR–JAK/STAT pathway; mutations in any of these components may weaken antiviral defense. We will apply sequencing and next-generation sequencing technologies to identify pathogenic genes in Taiwanese cohorts with severe viral infections and other severe infectious diseases, linking genetic variants to immune pathway dysregulation and developing translatable genetic diagnostic and precision therapy strategies, with the aim of making a meaningful impact on clinical prevention, prognostic assessment, and treatment.