Inflammasome Activation and Oxidative Stress in SARS-CoV-2 Infection and Symptomatic Rebound

Despite the efficacy of therapeutics and vaccines in reducing risk of severe coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections continue to occur and rebound symptoms after initial improvement have been well described. The mechanisms driving COVID-19 rebound remain unclear.

Critical inflammatory responses were assessed by Imagestream, flow cytometry, and single-cell RNA sequencing in peripheral blood mononuclear cells from vaccinated individuals presenting with early (3 days postinfection, n = 6) or late (8 days postinfection, n = 6) acute symptoms, and clinical rebound (16 days postinfection, n = 8), as well as healthy volunteers (HV, n = 7).

An overall decline in key inflammatory responses was observed in groups with longer time from symptom onset when compared to early acute infection. However, RNA sequencing revealed a partial resurgence of inflammatory, stress, and antiviral responses during clinical rebound, with a unique cluster of monocytes with greater activation of antigen presentation pathways and type I interferon signaling. Monocytes from patients with rebound COVID-19 also showed elevated inflammasome activation when compared to HV, along with an accumulation of oxidized lipids and decreased levels of glutathione, both hallmarks of the oxidative stress response. Inflammatory measurements positively associated with serum SARS-CoV-2 nucleocapsid antigen and inversely correlated with adaptive immune responses.

Our findings potentially reflect viral reappearance posttreatment in participants with clinical rebound and outline mechanisms by which rebound symptoms are typically milder than during acute presentations. Extending the antiviral treatment period and/or targeting inflammatory pathways could potentially prevent virological rebound or help mitigate associated symptoms. Clinical Trials Registration: NCT04401436.