Disease-promoting effects of type I interferons in viral, bacterial, and coinfections

Abstract

While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.

FIG. 1.

Multiple effects of IFN-αβ on immune and epithelial cells that can contribute to disease in specific infections. Only direct enhancing (green) and inhibitory (red) effects by IFN-αβ are color coded, secondary effects are in black. IFN-αβ can enhance production of IL-10, proinflammatory cytokines, and IL-27 and can block directly or indirectly the cytokines, IL-1, IL-12, IL-17, IFN-γ, and KC. Detrimental effects can be due to the suppression of antibacterial responses (IL-1, IL-17, IFN-γ, and KC) or to overstimulation of inflammation leading to damage by apoptosis of tissue cells or immune suppression by apoptosis of immune cells.

FIG. 2.

Moderate IFN-αβ responses to infection are protective, while excessive IFN-αβ amounts contribute to immunopathology. (A) Bell-shaped curve displaying resistance to influenza severity as a function of IFN-αβ responses, based on experimental findings in Davidson and others (2014) and other studies. High IFN-αβ-expressing mouse strains (eg, 129, DBA, agouti, and gray symbols) are highly susceptible to influenza, and genetic removal of IFN-αβ from such strains increases resistance (1). Conversely, exogenous addition of IFN-αβ to resistant, low IFN-αβ-expressing mouse strains (eg, C57BL/6, Balb/C, black, and white symbols) reduces their resistance to influenza (2). However, if the moderate IFN-αβ responses in C57BL/6 mice are genetically removed, influenza resistance is reduced (3). Linking these data points generates a dose–response curve (4) where moderate IFN-αβ responses protect and high IFN-αβ responses are detrimental. (B) Induction of antiviral (green) versus proinflammatory, antiproliferative, and apoptosis-promoting (red) genes as a function of IFN-αβ signal strength based on results and hypotheses, as reviewed in (Piehler and others 2012). We hypothesize that moderate IFN-αβ responses are protective in influenza infections as effective antiviral responses are balanced with moderate inflammation and apoptosis induction. Higher IFN-αβ signals increase inflammation and cell death, but do not further enhance induction of antiviral effectors.

FIG. 3.

Partial redundancy of types I and III IFNs in infection by influenza and other respiratory viruses. Both IFN-αβ and IFN-λ are induced upon influenza infection. Their effects depend on the distribution of their receptors: Epithelial cells express receptors for both IFN types, and both these IFNs can mediate the induction of the epithelial antiviral response (left). Immune cells express only IFN-αβ receptors and can be stimulated or inhibited by type I IFN (right). STAT1/2 is involved in signal transduction downstream of both type I and type III receptors. The degree and nature of immune activation determines whether the net result of all combined type I IFN-mediated effects is protective or pathogenic.