Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Abstract

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8 + T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response, but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Interfering with SARS-CoV-2: are interferons friends or foes in COVID-19?

“…This inflammatory response favors the recruitment and activation of multiple immune cells to the lungs, and it also results in systemic inflammation [ 7 , 8 ]. The virus potentially infects multiple human cell types in a number of organismal locations [ 9 , 10 ], but the damage and dysfunction that occur in several tissues are mainly linked to secondary immune-mediated responses, rather than to the presence of the virus itself [ 11 ] or to the viral load [ 12 ]. The term “cytokine storm” is still controversial [ 13 , 14 ], but severe COVID-19 is broadly recognized as an inflammatory disorder mediated by an uncontrolled immune response [ 14 , 15 ].…”

Molecular Phenomic Approaches to Deconvolving the Systemic Effects of SARS-CoV-2 Infection and Post-acute COVID-19 Syndrome

“…The complex shifts in metabolism observed in COVID-19 are not uniformly expressed, nor are they necessarily proportional to disease severity as simply classified by respiratory symptoms, although many changes are proportional to the lung damage which in its severe form is primarily immunologically driven. Indeed, the early immune responses are major determinants of individual clinical outcomes (Bergamaschi et al 2021). Recent immunological findings suggest that there might be limitations in the clinical value of early stage severity prediction because early CD8+ bystander cytotoxic T cell responses are responsible for the mitigation of severe lung injury and patients only have mild symptoms.…”

“…Recent immunological findings suggest that there might be limitations in the clinical value of early stage severity prediction because early CD8+ bystander cytotoxic T cell responses are responsible for the mitigation of severe lung injury and patients only have mild symptoms. Patients that fail to show strong CD8+ response appear to progress rapidly to severe respiratory disease, their disease trajectory having already have been set by the time of initial presentation at the clinic (Bergamaschi et al 2021). Given the narrow time windows involved for such severity progressions, which can be as little as a few hours from initial hospital presentation to critical care hospitalisation, there is insufficient time to test and intervene to modify the acute disease outcome.…”

An aberrant inflammatory response in severe COVID-19

“…IFN-Is are potent antiviral factors, but they also promote the activation of DCs and induction of cytotoxic CD8+ T cells. Accordingly, absence of an early robust CD8+ T cell response correlates with disease progression, suggesting that delayed priming of a potent antiviral immune response and poor early control of viral replication may contribute to a persistence of viral antigens or infectious virus that contributes to driving pathogenic inflammation ( Bergamaschi et al., 2021 ).…”