Type I interferons in infectious disease

Abstract

Type I interferons (IFNs) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. Type I IFNs are important for host defence against viruses. However, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. Conversely, they can lead to immunosuppression during chronic viral infections, such as lymphocytic choriomeningitis virus infection. During bacterial infections, low levels of type I IFNs may be required at an early stage, to initiate cell-mediated immune responses. High concentrations of type I IFNs may block B cell responses or lead to the production of immunosuppressive molecules, and such concentrations also reduce the responsiveness of macrophages to activation by IFNγ, as has been shown for infections with Listeria monocytogenes and Mycobacterium tuberculosis. Recent studies in experimental models of tuberculosis have demonstrated that prostaglandin E2 and interleukin-1 inhibit type I IFN expression and its downstream effects, demonstrating that a cross-regulatory network of cytokines operates during infectious diseases to provide protection with minimum damage to the host.

Figure 1. Pathways of type I interferon induction and receptor signalling.

Recognition of microbial products by a range of cell surface and intracellular pattern recognition receptors including TLRs and RIG-I can lead to type I IFN induction in cells, mediated by a number of distinct signalling pathways. Upon binding of type I IFNs to the IFNAR (IFNαβ receptor) multiple downstream signalling pathways can be induced, leading to a diverse range of biological effects. The canonical STAT1/STAT2/IRF9 (also known as the ISGF3 complex) signalling complex binds to ISRE elements in gene promoters, leading to induction of a large number of IFN-stimulated genes (ISGs). Type I IFNs can also signal through STAT1 homodimers, more commonly associated with the IFNγ signalling pathway. Other STAT heterodimers and homodimers may also be activated downstream, including STAT3, STAT4 and STAT5. Other signalling pathways that do not rely on JAK/STAT activity may also be activated, including mitogen activated protein kinases (MAPKs) and the phosphoinositide 3-kinase (PI3K) pathway, that leads to diverse effects on the cell.

Figure 2. Type I interferons during viral infection.

A. Infected cells of the vertebrate body produce type I IFNs in response to viral infection and/or contacting viral products (box, left side). Feedback of type I IFNs onto infected and bystander cells leads to the induction of IFN-stimulated genes (ISGs) that act to block the viral replicative cycle (inset box). Type I IFNs are also produced by, and act on, innate immune cells including professional antigen presenting cells (APCs), in response to viral infection and viral products. Type I IFNs acting on APCs can enhance their antigen presenting function as well as enhancing the antiviral function of adaptive cells including B cells, T cells and NK cells, which act to restrict viral infection through the production of antibody (B cells) and cytotoxic responses (T and NK cells). B. During chronic viral infection, type I IFNs can induce the production of immunosuppressive cytokines such as interleukin-10 (IL-10), together with expression on APCs of ligands, such as PDL1, for T cell inhibitory receptors such as PD1, leading to the suppression of T cell function and failure to clear infection. C. During acute viral infections such as influenza virus, type I IFN production by myeloid cells, such as plasmacytoid dendritic cells (pDCs) and inflammatory monocytes, leads to the upregulation of expression of the death receptor TRAIL on inflammatory monocytes and the TRAIL ligand DR5 on epithelial cells. TRAIL-expressing inflammatory monocytes then induce immune pathology and host morbidity and/or mortality through killing of epithelial cells.

Figure 3. Positive and negative effects of type I interferons during bacterial infection.

Low level autocrine IFNα/β signalling primes the production of interleukin-10 (IL-10), pro-inflammatory cytokines and antimicrobial effector mechanisms. 2b: type I IFN induces IL-1Rα, which in turn inhibits IL-1 signaling. IL-10 mediates a negative feedback loop, suppressing production of pro-inflammatory cytokines including IL-12, TNFα and IL-1α/β. Upon infection high levels of IFNα/β affecting myeloid cells can be contributed by autocrine production as well as from exocrine cellular sources. IFNα/β can also suppress pro-inflammatory cytokine production in an IL-10 independent manner. A major suppressive mechanism of type I IFN is down-regulation of the IFNγR, thus abrogating IFNγ dependent host protective immune responses. IFNα/β signalling can promote high levels of IL-10 production as well as the induction of pro-apoptotic factors. IL-1α/β induces COX-2 dependent PGE2. PGE2 and IL-1 inhibit type I IFN expression and downstream effects

Figure 4. Mechanisms of interferon action in non-viral infections.

The diagram indicates the mechanistic processes that are influenced by IFNα/β during bacterial infections. Arrows indicate whether IFNα/β promote, suppress or have variable, context dependent, effects on the associated process. For each process, infections in which IFN-mediated effects may be manifest are shown. In green are those infections where IFNα/β are thought to be protective and in red those where IFNα/β have host detrimental effects. For processes in which IFNs have variable effects the relevant effect is shown for each described disease by an arrow indicating promotion or suppression. For example, IFNα/β have variable effects on chemokine production and cell migration. In S. pyogenes infection (where IFNα/β is protective), IFNα/β have promoting effects on chemokine production and cell migration.