SARS-CoV-2, COVID-19 and the Ageing Immune System

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of ageing have highlighted how ageing pathways control not only lifespan but also healthspan, the healthy years of life. Here, we discuss the ageing immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target ageing-associated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in the elderly but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

Figure 1.. Factors that contribute to inflammageing and immunosenescence.

Both exogenous and cell-endogenous factors contribute to chronic inflammation with age, which is primarily mediated by immune cells and senescent cells. Senescent cells persist and accumulate during ageing, and they display an abnormal secretory phenotype, characterized by the production of inflammatory mediators, matrix metalloproteinases (MMPs), fibronectin, and reactive oxygen species. These inflammatory mediators contribute to inflammageing, which, over time, affects immune cell function, promoting immunosenescene. The endogenous and exogenous factors listed here can also directly affect the inflammatory potential of the immune system, which further promotes a feed-forward loop of inflammageing and immunosenescence.

Figure 2.. Immune response patterns and clinical disease courses for mild and severe COVID-19.

For (a) mild COVID-19 and (b) severe COVID-19, graphs show the general disease course timeline and the magnitude of the innate (green) and adaptive (purple) immune responses over time. Dashed lines represent the time course for response in patients with pre-existing adaptive immunity. For (b) severe COVID-19, there are five main points of interest in the immune response that could be influenced by an ageing immune system: 1) heightened basal inflammation (inflammageing) at the point of SARS-CoV-2 inoculation may predispose the elderly to an already pro-inflammatory local environment; 2) innate immune cell dysfunction associated with aging may alter early immune responses; 3) delayed and/or diminished adaptive responses due to poor naive clonal diversity, weak or ineffective pre-existing immunity, and poor T cell priming; 4) altered T effector function and antibody responses due to immunosenescence; and 5) the possibility of a reduced memory response and potential long-lasting effects on the immune system that may further promote immunosenescent phenotypes.

Figure 2.. Immune response patterns and clinical disease courses for mild and severe COVID-19.

For (a) mild COVID-19 and (b) severe COVID-19, graphs show the general disease course timeline and the magnitude of the innate (green) and adaptive (purple) immune responses over time. Dashed lines represent the time course for response in patients with pre-existing adaptive immunity. For (b) severe COVID-19, there are five main points of interest in the immune response that could be influenced by an ageing immune system: 1) heightened basal inflammation (inflammageing) at the point of SARS-CoV-2 inoculation may predispose the elderly to an already pro-inflammatory local environment; 2) innate immune cell dysfunction associated with aging may alter early immune responses; 3) delayed and/or diminished adaptive responses due to poor naive clonal diversity, weak or ineffective pre-existing immunity, and poor T cell priming; 4) altered T effector function and antibody responses due to immunosenescence; and 5) the possibility of a reduced memory response and potential long-lasting effects on the immune system that may further promote immunosenescent phenotypes.

Figure 3.. An ageing innate immune system may predispose a patient to severe COVID-19.

Consequences of the virus are indicated by black arrows, while consequences of ageing are indicated by red arrows. SARS-CoV-2 first enters cells by binding to ACE2, and viral entry then leads to the shedding of ACE2. Ageing may also be associated with reduced expression of ACE2, and the low expression of ACE2 after infection potentially mediates a pro-inflammatory state through the production of angiotensin (Ang) II. Severe COVID-19 has also been correlated with reduced type I IFN responses, a defect which may be compounded by aberrant type I IFN signaling with age. This could be made worse by the notable reduction in total number of pDCs found in severe COVID-19 patients. Aged pDCs also have a reduced ability to produce type I IFNs, and the pro-inflammatory nature of the SASP in older individuals desensitizes JAK/STAT signaling in innate immune cells. All of this would compound the loss of type I IFN signaling during severe COVID-19, ultimately leading to reduced expression of antiviral IFN-stimulated genes (ISGs) and permitting enhanced viral propagation. This viral replication leads to cell death and damage, causing the production of immunostimulatory DAMPs and PAMPs. Signaling in response to these signals generally activates the NF-κB transcription factor, which is also the main immune signaling pathway engaged by SASP mediatorsand the persistent basal stimulation of pattern recognition receptors in older adults. NF-κB signaling promotes production of pro-inflammatory cytokines. DAMPs linked to both aging and viral infection can also trigger activation of inflammasomes such as NLRP3, potentiating cytokines such as IL-1β and IL-18, as well as triggering further cell death through pyroptosis. SASP mediators and the autoimmune-prone environment associated with aging may also predispose aged individuals to a prothrombotic environment, and thrombosis and inflammation continue to promote one another in a feed-forward loop which further contributes to the hyperinflammatory, pathophysiological innate response that causes devastating outcomes observed in severe COVID-19.

Figure 4.. Ageing adaptive immune system responses during severe COVID-19.

a-d, It has been hypothesized that a delayed and/or weak adaptive immune response helps drive the dysregulated and continued recruitment of neutrophils and monocytes. These cells facilitate a non-specific and highly destructive hyperinflammatory response that contributes to the outcomes observed in patients with severe COVID-19. Failures of the adaptive system would begin at sites of infection (a), where DCs are initially activated by PAMPs and DAMPs in response to SARS-CoV-2. Patients with severe COVID-19 have DCs with a reduced maturation profile. (b) Ageing also negatively affects DC maturation, furthering the potential for improper priming of naive T cells in lymph nodes in older adults. There appears to be a loss of GC reactions and atrophy of the secondary lymphoid organs (SLOs) in fatal cases of COVID-19. These factors, combined with decreased CD40L expression on aged CD4+ T cells and reduced AID expression in aged B cells, could culminate in greatly impaired high-avidity, long-lasting antibody production that is dependent upon the success of GC reactions. Reductions in levels of GC reactions are also linked to extrafollicular and age-associated B cell (ABC) responses, which may potentiate ‘lupus-like autoimmune inflammation’. As we age, the naive TCR repertoire also decreases, making DC accessibility to SARS-CoV-2-specific naive T cells potentially even more challenging, delaying priming responses. (c,d) Lymphopenia is also strongly associated with severe COVID-19 outcomes. The aged microenvironment may contribute to this phenotype, as the SASP mediators IL-6 and TNFα can cause enhanced T cell apoptosis. Furthermore, the presence of virtual memory CD8+ T cells at sites of SARS-CoV-2 infection may contribute to a hyperinflammatory response through the action of bystander cytotoxicity, which occurs in a non-antigen-specific manner and can be highly destructive if left unregulated. AID, activation-induced cytidine deaminase; FDC, follicular dendritic cells; SHM, somatic hypermutation; Teff cell, effector T cell. Immune responses to the virus are indicated by black arrows, and consequences of aging are shown by red arrows.