Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes

Abstract

As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.

Keywords: aging; immunopathology; inflammation; monocyte/macrophages; type I IFN; type II IFN; type III IFN.

Figure 1

Diagram of type I IFN induction and mechanisms of impaired induction in aging. (A) Recognition of viral dsRNA in the cytosol by RIG-1 or MDA-5 leads to IRF3 activation of TRAF-3. Aging is associated with the degradation of TRAF-3 and the reduced phosphorylation of IRF3. IRF3 mediates the transcription of type I IFNs and IRF8, which feedbacks to amplify the expression of type I IFNs. (B) TLR7 and 9 recognition of viral ssRNA and CpG DNA in pDCs induces the activation of MyD88 and TRAF6, leading to the activation of IRF5 and 7, and the translocation to the nucleus for the transcription of type I IFNs. Aging leads to the reduction in pDC numbers in circulation, TLR7/9 expression, and IRF7 adaptor expression.

Figure 2

Impaired type I IFN induction in aging impairs viral clearance and promotes immunopathology following infection. Top: reduced IFN-α/β production in elderly individuals in the upper respiratory tract impair control of early viral replication. Middle left: type I IFN production of epithelial cells and myeloid cells regulates immune response to infection to promote viral clearance. Type I IFN responses induce inflammatory monocyte/macrophage (IMM) recruitment and activation, subsequently inducing NK cell recruitment and activation. IMM production of IL-12/15/18 promotes DC maturation to induce T and B cell functions. Bottom left: immune-mediated viral clearance, as well as macrophage-mediated resolution of inflammation promotes immune tolerance to infection. Middle right: Suppressed type I IFN induction in elderly individuals impairs the control of excessive IMM and neutrophil infiltration, and cytokine storm. Bottom right: IMM and neutrophils mediate significant damage to the airways and cause disease pathology to infection. Created with BioRender.com.