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. 2026 Jan 20:jiag037.
doi: 10.1093/infdis/jiag037. Online ahead of print.

Inflammasome activation and oxidative stress in SARS-CoV-2 infection and symptomatic rebound

Silvia Lucena Lage  1 , Joseph M Rocco  1 , Cihan Oguz  2 , Francisco Otaizo-Carrasquero  3 , Adam Rupert  4 , Kristin L Boswell  5 , Brian P Epling  1 , Logan Cook  1 , Eduardo Pinheiro Amaral  6 , Elizabeth Laidlaw  1 , Frances Galindo  1 , Richard A Koup  5 , Princy Kumar  7 , Rita Poon  8 , Glenn W Wortmann  9 , Andrea Lisco  1 , Maura Manion  10 , Irini Sereti  1
Affiliations

Inflammasome activation and oxidative stress in SARS-CoV-2 infection and symptomatic rebound

Silvia Lucena Lage et al. J Infect Dis. .

Abstract

Background: Despite the efficacy of therapeutics and vaccines in reducing risk of severe COVID-19, SARS-CoV-2 infections continue to occur and rebound symptoms after initial improvement has been well-described. The mechanisms driving COVID-19 rebound remain unclear.

Methods: 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 [EA, 3 days post-infection (PI), n=6] or late (LA, 8 days PI, n=6) acute symptoms and clinical rebound (rebound, 16 days PI, n=8), as well as healthy volunteers (HV, n=7).

Results: An overall decline in key inflammatory responses is observed in groups with longer time from symptom onset when compared to EA 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 IFN 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, suggesting adaptive immunity limits inflammation in patients with rebound.

Conclusions: Our findings potentially reflect viral reappearance post-treatment in participants with clinical rebound and outline mechanisms why 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.

Keywords: COVID-19 rebound; Inflammasome; SARS-CoV-2 breakthrough infection; monocytes; oxidative stress.

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