Differential roles of interferons in innate responses to mucosal viral infections

Abstract

Interferons (IFNs) are among the first vertebrate immune pathways activated upon viral infection and are crucial for control of viral replication and dissemination, especially at mucosal surfaces as key locations for host exposure to pathogens. Inhibition of viral establishment and spread at and from these mucosal sites is paramount for preventing severe disease, while concomitantly limiting putative detrimental effects of inflammation. Here, we compare the roles of type I, II, and III IFNs in regulating three archetypal viruses - norovirus, herpes simplex virus, and severe acute respiratory virus coronavirus 2 (SARS-CoV-2) - which infect distinct mammalian mucosal tissues. Emerging paradigms include highly specific roles for IFNs in limiting local versus systemic infection, synergistic activities, and a spectrum of protective versus detrimental effects of IFNs during the infection response.

Keywords: IFN-alpha/beta; IFN-gamma; IFN-lambda; SARS-CoV-2; herpesvirus; interferon-stimulated genes; interferons; mucosal viruses; norovirus; viral antagonism.

Figure 1

Overview of interferon signaling pathways in vertebrate hosts. Production of interferons (IFNs) begins with the binding of viral molecules, such as genomic nucleic acids, to either cell surface or intracellular pattern recognition receptors (PRRs) [18,19]. The resulting signaling cascade activates transcription and secretion of IFNs, which then bind to their associated IFN receptor on the same and nearby cells. Binding of IFNs to their receptors activates a signal cascade by Janus tyrosine kinases (JAK) and tyrosine kinase (TYK) that leads to the phosphorylation of STAT1 and/or STAT2 [9,15]. For type I and III IFNs, STAT1 and STAT2 complex with IRF9 and bind to IFN-stimulated response elements (ISREs) to express IFN-stimulated genes (ISGs). For type II IFNs, phosphorylated STAT1 dimers bind to gamma-activated site (GAS) elements for ISG production [9,15]. In turn, ISGs mediate antiviral effects directly within infected cells, or further induce innate and adaptive immune responses [3,120]. Figure created using BioRender (https://biorender.com/). Abbreviation: ISG, IFN-stimulated gene.

Figure 2

Key figure. Key roles for type I, II, and III interferons in mucosal antiviral responses in mice and humans. (A) Norovirus initiates infection within the gastrointestinal tract, wherein type III interferons (IFNs) are key for restricting viral growth [30]. Type I IFNs restrict dissemination of the virus from the gut to distal sites such as the liver and brain, wherein type II IFN further controls replication [69,89]. (B) Herpes simplex virus infections initiated in the female reproductive tract are controlled at the site of infection by type III IFNs, while type I IFNs drive inflammation [29,60]. Dissemination from this mucosal tissue to the central nervous system (CNS) is restricted by type I IFNs [32,73]. Herpesviruses undergo latency, remaining mostly transcriptionally silent within neurons, with reactivation of the virus from latency restricted by type II IFN [92]. (C) SARS-CoV-2 is restricted within the respiratory tract by type I and III IFNs [83,84,113]. Conversely, type I IFNs may be drivers of inflammation in the respiratory tract during SARS-CoV-2 infection [28,83,86]. The role of type II IFN is currently less understood, but it may be proviral in some sites by inducing expression of the viral receptor and may also drive inflammation [100]. Figure created using BioRender (https://biorender.com/). Abbreviation: SARS-CoV-2, severe acute respiratory virus coronavirus 2.