Interferon system deficiencies exacerbating severe pandemic virus infections

Abstract

Pandemics are caused by novel pathogens to which pre-existing antibody immunity is lacking. Under these circumstances, the body must rely on innate interferon-mediated defenses to limit pathogen replication and allow development of critical humoral protection. Here, we highlight studies on disease susceptibility during H1N1 influenza and COVID-19 (SARS-CoV-2) pandemics. An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled virus replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with autoantibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19. We discuss key questions surrounding how such autoantibodies develop and function, as well as the general implications of diagnosing interferon deficiencies for personalized therapies.

Keywords: COVID-19; autoantibodies; disease severity; host genetics; influenza; interferon; pandemic virus.

Figure I

Overview of the type I and type III interferon (IFN) responses. Simplified signaling cascades leading to transcription of type I/III interferon genes following infection with an RNA virus (left panel). Simplified signaling cascades leading to transcription of interferon-stimulated genes (ISGs) following type I/III interferon stimulation (right panel). RIG-I, MDA-5, TLR3, TLR7, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, IFNAR2, IFNLR1, IL10RB, JAK1, TYK2, STAT1, STAT2, and IRF9 are human interferon system components involved in recognizing virus infections, stimulating interferon production, or mediating antiviral signaling; ISRE, interferon-stimulated response element.

Figure I

Schematics of IFITM3 antiviral activity and functional polymorphisms. (A) IFITM3 at the endosomal membrane blocks entry of viruses, such as influenza A virus. (B) IFITM3 at the plasma membrane limits subsequent infectivity of budding viruses, such as HIV-1. (C) The indicated single-nucleotide polymorphisms (SNPs) in human IFITM3 impact its antiviral function and influence control of virus replication. IFITM3, interferon-induced transmembrane protein 3.

Figure 1

Do neutralizing autoantibodies against type I interferons lead to uncontrolled virus replication? Simplified representation of type I interferon (IFN)-mediated inhibition of virus replication triggered by IFNα or IFNω binding to their cognate heterodimeric receptor (IFNAR1/IFNAR2) (left panel). Autoantibodies that bind IFNα or IFNω and prevent their interaction with IFNAR1/IFNAR2 are termed ‘neutralizing’ and could limit the antiviral action of type I interferons leading to uncontrolled virus replication (right panel).

Figure 2

Key Figure. The high proportion of severe COVID-19 patients with autoantibodies against type I interferons raises important questions. Autoantibodies against type I interferons have been found in 5–10% of individuals who suffer from severe COVID-19. There are several important questions that still need to be addressed regarding how these autoantibodies are triggered (right side), and what these autoantibodies mean for virus susceptibility and future personalized therapies (left side).