The coronavirus disease (COVID)-19 pandemic has elicited a swift response by the scientific community to elucidate the pathogenesis of severe acute respiratory syndrome coronavirus (SARS-CoV)-2-induced lung injury and develop effective therapeutics. Clinical data indicate that severe COVID-19 most commonly manifests as viral pneumonia-induced acute respiratory distress syndrome (ARDS), a clinical entity mechanistically understood best in the context of influenza A virus-induced pneumonia. Similar to influenza, advanced age has emerged as the leading host risk factor for developing severe COVID-19. In this review we connect the current understanding of the SARS-CoV-2 replication cycle and host response to the clinical presentation of COVID-19, borrowing concepts from influenza A virus-induced ARDS pathogenesis and discussing how these ideas inform our evolving understanding of COVID-19-induced ARDS. We also consider important differences between COVID-19 and influenza, mainly COVID-19's protean clinical presentation and associated lymphopenia, the contrasting role of interferon-γ in mediating the host immune response to these viruses, and SARS-CoV-2's tropism for vascular endothelial cells, commenting on the potential limitations of influenza as a model for COVID-19. Finally, we explore hallmarks of aging that could explain the association between advanced age and susceptibility to severe COVID-19
Insights into COVID-19-induced ARDS The heterogeneity associated with COVID-19's clinical presentation has prompted the conceptualisation of novel paradigms of respiratory disease in an effort to explain the observed variability and individualise clinical management of COVID-19. Nevertheless, a recent cohort study reported that as many as 85% of ICU patients with COVID-19 meet the Berlin Criteria definition of ARDS and that well-established supportive interventions for ARDS, such as low tidal volumes and prone ventilation, resulted in significant improvement in oxygenation and lung compliance. It is therefore reasonable to explore other causes of viral pneumonia-induced ARDS to glean insights into severe COVID-19 while we await more disease-focused data. Accordingly, there is evidence suggesting both parallels and contrasts between influenza and SARS-CoV-2 infections.
Global immune signature of SARS-CoV-2 Early work performed to characterise COVID-19's host immune response suggested an immune signature consisting of elevated serum cytokines (particularly IL-1β, IL-6, and TNF-α), impaired interferon responses, and peripheral lymphopenia as markers of severe disease; other associated inflammatory serum markers include elevated levels of ferritin, lactate dehydrogenase, d-dimer, C-reactive protein, and coagulation factors. Furthermore, transcriptional profiling of lung epithelial cells following SARS-CoV-2 and influenza infections in vitro revealed similar dampening of IFN-I and -III signalling in the host response to both of these viruses and a shared cytokine signature (including IL-6 and TNF-α). In contrast, the SARS-CoV-2-specific immune signature identified in vitro was characterised by high IFN-II signalling and chemokine expression relative to influenza.
Impaired interferon-I and -III responses Both COVID-19 and influenza are associated with an impaired IFN-I and -III host response relative to other viruses, and COVID-19 severity correlates with the degree of impairment. The influenza and SARS-CoV genomes code for the nonstructural protein 1 (NS1), which antagonises IFN-I and -III signalling; similarly, the SARS-CoV-2 proteins ORF6, ORF8 and its nucleocapsid also inhibit IFN-I signalling in vitro. The conserved nature of NS1, combined with COVID-19's associated IFN-I and -III impairment, suggest that SARS-CoV-2 has shared virulence factors with SARS-CoV that are also recapitulated in influenza infection. IFN-I modulates the pro-inflammatory response of macrophages, making it reasonable to hypothesise that downregulation of IFN-I could explain the hyperinflammatory state associated with COVID-19.
However, pharmacologic inhibition of IFN-I signalling in SARS-CoV-2-infected cells in vitro did not increase cytokine production, suggesting that impaired IFN-I secretion is insufficient to explain severe COVID-19's hyperinflammatory state. IFN-III (or IFN-λ) shares similar functions with IFN-I but is more potent in promoting influenza clearance without inducing excessive inflammation. IFN-III is essential in mediating the initial response to influenza, holding non-redundant roles in regulating the tissue-destructive properties of neutrophils as well as in potentiating CD8+ memory T cell immunity against influenza by inducing the migration of dendritic cells to draining lymph nodes. These observations have made pharmacologic IFN-λ a candidate for the management of COVID-19, although murine studies of IFN-λ's deleterious effect on the host's susceptibility to secondary bacterial infections raise concerns about its safety. Nevertheless, given the observation that these pro-inflammatory molecules are able to limit SARS-CoV-2 replication in vitro, ongoing clinical trials are ascertaining the therapeutic benefit of exogenous IFN-I and IFN-III administration for COVID-19.
Cytokine storm as driver of COVID-19 severity The overlap in secreted cytokines in response to SARS-CoV-2 and influenza can be explained by the presence of viral RNA in the host cell's cytoplasm during the replication cycle of both viruses, which likely induces the activation of similar intracellular anti-viral pathways and subsequent recruitment of similar immune cells to the respiratory epithelium. SARS-CoV-2's pro-inflammatory immune signature has been likened to macrophage-activation syndrome (MAS), a life-threatening clinical entity observed in autoimmune diseases and mimicked in many viral infections, including influenza. MAS is associated with impaired cytolytic activity of NK cells and specific CD8+ T cell subpopulations, which are tasked with lysing infected host cells to prevent prolonged secretion of inflammatory cytokines by compromised cells. Such impairment in cell-mediated lysis is driven by high levels of IL-6, establishing a vicious cycle of cytokine-driven pro-inflammatory cytokine secretion. Therefore, elevated IL-6 levels and their association with severe disease are thought to reflect an over-exuberant inflammatory response that lacks proper regulation and resolution, mimicking an MAS-like pathologic state.
Vasculopathy of COVID-19 and implications for the cytokine storm hypothesis SARS-CoV-2's expanded tropism poses a substantial challenge when attempting to use influenza's associated cytokine storm to derive conclusions about COVID-19's potential virulence mechanisms. Importantly, available data from patients who succumbed to COVID-19 suggest that SARS-CoV-2 infects endothelial cells to cause inflammation (endothelialitis). This observed endothelialitis supports the idea that SARS-CoV-2 has tropism for vascular endothelial cells, which express the ACE receptor. Moreover, viral cytotoxicity could be playing a larger role in mediating severe COVID-19 than in influenza, since post-mortem detection of replicating virus is less frequent in the latter. These findings could also explain the multi-system organ failure and hypercoagulable state associated with severe COVID-19, since local pulmonary endothelialitis would result in activation of the coagulation cascade and exuberant production of endothelium-derived pro-inflammatory cytokines without the need to invoke an MAS-like pathologic state. Moreover, reported plasma IL-6 levels in COVID-19 patients appear to be significantly lower on average (10- to 40-fold) when compared with those reported in other non-COVID-19 ARDS cohorts that display signs of a cytokine storm. These observations lend less credibility to the hypothesis that elevated serum cytokines are driving the unprecedented morbidity and mortality observed in severe COVID-19, suggesting instead that they are consequences of local vasculopathy. Of note, a clinical trial exploring the therapeutic benefit of monoclonal IL-6 receptor antibodies for COVID-19 was recently discontinued in the absence of a detectable benefit.
The dichotomous role of interferon-II There are important differences between influenza and COVID-19 regarding the role of IFN-II (or IFN-γ) in driving disease severity. Previous studies on IFN-γ's role in the host response to influenza revealed that attenuation of IFN-γ signalling during the late phases of inflammation can improve clinically-relevant outcomes by promoting survival of CD8+ T cells. This protective effect of low IFN-γ in influenza differs with the inverse correlation observed between levels of IFN-γ produced by CD4+ T cells and the severity of COVID-19. Moreover, SARS-CoV-2 was shown to induce a stronger IFN-γ response in vitro compared with influenza, suggesting that IFN-γ might play a larger role in the host immune response to COVID-19. Some have suggested that the IL-6-to-IFN-γ ratio could be used as a clinical tool to stratify patients by their relative risk of developing severe COVID-19, and preliminary analyses of this ratio as a risk-stratifying measure for severe COVID-19 showed promising results. Nevertheless, a better understanding of the role of IFN-γ in driving severe disease and the validation of the IL-6-to-IFN-γ ratio in larger cohorts will be required before its deployment as a reliable clinical tool.
COVID-19-associated lymphopenia Severe COVID-19 is associated with lymphopenia that disproportionately affects the T rather than B cell compartment. Similar changes in lymphocyte counts occur in other viral infections via mechanisms such as TNF-α-mediated inhibition of lymphocyte recirculation. In fact, IL-6 inhibition improved the lymphopenia of severe disease in a subset of COVID-19 patients, suggesting a role for elevated serum cytokines in depleting peripheral T lymphocytes. Nevertheless, recent immune profiling of COVID-19 patients revealed that the T cell compartment, although more strongly affected in severe versus moderate COVID-19, is still significantly diminished in the peripheral blood of COVID-19 patients compared with cases of non-COVID-19 pneumonia. This finding suggests that cytokine excess is not the only causal factor for the lymphopenia of COVID-19. Another potential explanation for COVID-19-associated lymphopenia is the excessive recruitment and sequestration of lymphocytes in the lung. In support of this hypothesis, post-mortem examination of independent cohorts of COVID-19 patients identified pulmonary lymphoid infiltrates in a subset of cases, and similar observations were made in bronchoalveolar lavage fluid samples from patients with both mild and severe COVID-19. Finally, some hypothesise this lymphopenia to be a direct consequence of the expanded tropism of SARS-CoV-2, which could confer cytotoxicity to T cell populations; however, such tropism remains unverified. As lymphopenia is being considered for patient risk stratification, elucidating the etiology of COVID-19-associated lymphopenia is crucial for our understanding of COVID-19 pathogenesis and efforts to identify patients at risk of developing severe disease.
Transmissibility profile and host risk factors for severe disease Current models of COVID-19's transmissibility recapitulate an influenza-like profile of viral shedding, suggesting that contact precautions for influenza could prove efficacious in the context of COVID-19. Importantly, there are key differences between these two viruses with respect to identified host risk factors for severe disease. For example, influenza-induced ARDS carries a female predominance, while COVID-19-induced ARDS is mostly associated with male sex, suggesting that they exploit different host susceptibilities to enhance their pathogenicity. Regardless, advanced age still remains the main predictor for the development of severe disease associated with both pathogens, signifying that our knowledge of advanced age as a risk factor for influenza-induced ARDS can inform our understanding of age in predisposing to severe COVID-19.
Potential mechanisms through which aging drives severe COVID-19 Advanced age is associated with an increased risk of developing life-threatening infections. Indeed, almost 90% of influenza-related mortality and a disproportionate fraction of COVID-19-related mortality occurs in individuals over the age of 65. This age-related susceptibility to severe disease does not arise solely because of prolonged exposure to environmental and host risk factors, such as tobacco smoke or primary hypertension, but also through the development of maladaptive physiological processes that affect an individual's ability to maintain homeostasis when faced with a stressor. These processes have been coined the hallmarks of aging and have been broadly associated with an age-related susceptibility to stress, also known as homeostenosis. The increasingly older world population and its myriad age-related comorbidities have generated substantial interest in understanding the pathophysiology of these hallmarks of aging, particularly as they relate to the risk of severe COVID-19. While their influence has not been elucidated in the context of SARS-CoV-2 infection, our current knowledge of their role in influenza provides insight into why aging is a risk factor for the development of severe COVID-19
Epigenetic alterations and mitochondrial dysfunction Advanced age is associated with changes in the epigenetic and metabolic landscape of immune cells that mediate the host response to viral pneumonia-induced ARDS, including Treg cells. The pro-repair function of Treg cells is associated with DNA hypomethylation of Treg cell lineage-specific loci. Indeed, inhibition of DNA methyltransferases in Treg cells accelerates lung injury resolution in a murine influenza model, suggesting that DNA methylation is required to maintain the Treg cell lineage over the lifespan but impairs Treg cell reparative function after lung injury. While alterations in Treg cell function and numbers have been shown to occur with aging, the mechanisms through which these changes occur remain unclear; however, recent studies suggest they could be mediated by the accumulation of toxic metabolites and reactive oxygen species caused by the mitochondrial dysfunction associated with aging. For example, intracellular accumulation of the metabolite L-2-hydroxyglutarate from its synthesis during hypoxia and other states of mitochondrial dysfunction induces DNA hypermethylation and impairs suppressive function in Treg cells. Such metabolite accumulation could ultimately inhibit Treg cell-dependent ARDS recovery by repressing the expression of key loci associated with Treg cell pro-resolution and pro-repair pathways. Given the age-related phenomenon of mitochondrial dysfunction, irrespective of its proximate cause, it is plausible that similar phenomena are occurring across other cell types also required for viral ARDS resolution.
Telomere attrition and cellular senescence Aging is associated with the erosion of chromosomal telomeres from successive cellular replication (telomere attrition) and the concomitant cell cycle arrest of somatic cells (cellular senescence), including monocytes and lymphocytes. Monocytes from aged mice suffer from an inability to properly phagocytose bacterial pathogens, while producing significantly higher levels of TNF-α relative to young mice. These findings correlate with the telomere length of monocytes, which are shorter in the elderly, suggesting an age-related impairment in pathogen clearance and excessive TNF-α-mediated apoptosis that is in part mediated by telomere attrition. These age-related phenomena also affect naïve T and B cell numbers, manifesting as low peripheral blood counts of these cells in older hosts. Coupled with the process of thymic involution, age-related depletion of naïve T cell counts poses a substantial impediment for the adaptive immune system's ability to generate antigen-specific memory lymphocytes. Accordingly, a recent GWAS of genetic factors linked to severe COVID-19 susceptibility identified a risk allele associated with decreased levels of CXCR6 expression, which is a chemokine receptor expressed in tissue resident memory T cells. This finding supports the hypothesis that impaired memory T cell function predisposes to developing severe COVID-19. Age-related naïve T cell deficiency is also hypothesised to play a role in the prolonged hospital stays and increased susceptibility to severe disease in the aging population affected by influenza-induced ARDS. Finally, naïve T cell depletion also underlies the decreased efficacy of seasonal influenza vaccines observed with increasing age, restricting preventive therapeutic alternatives for older adults.
Altered intercellular communication The replicative senescence related to aging affects a variety of somatic cells and is associated with a shift toward a basal, chronic secretion of pro-inflammatory cytokines, a phenomenon termed the senescence-associated secretory phenotype (SASP). According to the senescence hypothesis, accumulation of these SASP-like cells throughout aging results in the persistent recruitment and activation of effector immune cells that perturb the local communication of the pro- and anti-inflammatory arms of the immune system, inducing tissue damage and impeding tissue repair. Accordingly, selective depletion of stress-induced senescent cells in vivo attenuated the SASP-related transcriptional signal following acute lung injury and improved physical function in mice, suggesting that the accumulation of senescent alveolar epithelial cells ultimately compromises the host's ability to properly recover from acute lung injury. Such pro-inflammatory states may also explain the predisposition to many age-associated pathologies, including primary hypertension, the comorbidity most strongly correlated with an individual's risk for developing severe COVID-19.
Concluding remarks Our evolving understanding of COVID-19 suggests that the pathogenesis of influenza provides insights into COVID-19, particularly with regard to the impaired IFN-I and -III host response. However, findings in influenza fall short in explaining severe COVID-19's distinct clinical course, endothelialitis, the role of IFN-II, and the lymphopenia associated with severe COVID-19. We suggest that such differences between these two infections represent SARS-CoV-2-specific virulence mechanisms that, if elucidated, could inform the development of novel therapeutic strategies. Therefore, we contend that these differences need to be accounted for and should be a focus for ongoing research efforts. We also speculate that the severe COVID-19-specific immune signature, coupled with age-related maladaptive phenomena, could impede the host's ability to dampen the inflammatory phase of severe COVID-19 and resolve lung injury, contributing to the protracted ICU care episodes and the attendant morbidity and mortality associated with prolonged ICU stays among older adults. Given the interdependent and synergistic nature of these hallmarks of aging, we suggest that these hallmarks' influence on relative susceptibility to developing severe COVID-19 should be studied in concert. Ultimately, the mechanistic associations between the biology of aging and the relative susceptibility to severe viral pneumonia-induced ARDS carry substantial clinical implications that require careful consideration in future efforts to develop population-specific preventive and therapeutic interventions for COVID-19.
Reference & source information: https://erj.ersjournals.com/
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