Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection

Abstract

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2–infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.

Distinct Type I Interferon Subtypes Differentially Stimulate T Cell Responses in HIV-1-Infected Individuals

“…The type I IFN family comprises multiple IFNa subtypes, which are highly conserved in their amino acid sequence. Despite their sequence homology, they all differ in their biological activity such as their antiviral, immunomodulatory, and anti-proliferative properties (1)(2)(3)(4)(5) possibly due to their different affinities to the type I IFN receptor (IFNAR) (6), as well as differences concerning downstream signaling events (1) leading to the induction of distinct IFN-stimulated gene (ISG) expression patterns (3,4,7).…”

B cells, BAFF and interferons in MIS-C

“…To explore the hyperinflammatory signature of MIS-C we measured IFN-α, IFN-γ and IFN-λ in the serum of 50 patients with MIS-C sampled shortly after admission to hospital, before administration of immunosuppressive therapy, and compared them to the sera of healthy children who underwent COVID-19 4-6 weeks prior to sampling and had no signs of MIS-C. We saw no significant changes in IFN-α (t test with Welch's correction p = 0.27) and IFN-λ levels (p = 0.33) (Fig 1A, C), therefore our data suggests that lingering type I and III interferon inflammation are not robust driving factors behind MIS-C pathogenesis, despite their role in fight against the SARS-CoV-2 infection proper 19,21,22 . On the other hand, IFN-γ was significantly elevated in MIS-C compared to healthy post-COVID children (p = 0.0004) (Fig 1B).…”

Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond

“…The suboptimal therapeutic effects of IFN-α2 and IFN-β encouraged researchers to explore the functional diversity of IFN-α subtypes for antiviral treatment against SARS-CoV-2 and influenza viruses [ 173 , 174 , 175 , 176 ]. These reports demonstrate the induction of distinct and subtype-specific transcriptomic landscapes which translate into virus-specific antiviral properties in different tissues, further suggesting their individual therapeutic potential [ 177 ].…”