Targeting of the CD80/86 proinflammatory axis as a therapeutic strategy to prevent severe COVID-19

Abstract

An excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.

COVID-19 Treatment—Current Status, Advances, and Gap

“…Its activity in modulating T-cell activation and downregulating cytokines production while monitoring the downstream immune response has drawn interest in considering it as a drug for COVID-19 [ 45 ]. Systemic response of abatacept also showed high significant antagonism with COVID-19 severity, further supporting the use of abatacept to prevent severe COVID-19 [ 46 ]. Furthermore, a phase 3 ACTIV-1 Immune Modulators trial involving 1022 patients showed that a 10 mg/kg dose of abatacept administration reduced the mortality rate by 37.4%.…”

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

“…AURKB controls cell cycle progression and proper chromosome segregation, and may play a role in SARS CoV-2 nucleocapsid phosphoprotein (N-protein) mutation since important Aurora kinase B phosphorylation sites (R203 and G204) are commonly mutated residues of N-protein [54,73]. TYMS is involved in the CD80/86 proinflammatory axis, and is upregulated in severe COVID-19 patients [74]. Dysregulation of this gene pathway may contribute to downstream effects of antigen presentation and sustained T cell activation [75].…”

Immunomodulatory mechanisms of abatacept: A therapeutic strategy for COVID-19

“…Our study suggested that abatacept was a potential strategy for severe COVID-19 based on the intersection of DEGs, the resemblance of antirheumatoid mechanisms and immune-inflammatory responses in COVID-19. Abatacept treatment could be a critical way to avoid an inflammatory storm in COVID-19 ( 13 ). Compared with the study of Julia et al, we conducted an analysis using larger sample size, identified potential biomarkers, and explored deeper mechanisms through which abatacept treats CODVID-19.…”

“…Drug repurposing is a strategy for identifying new indications for approval. Evidence has been provided for abatacept as a candidate therapeutic approach to prevent severe COVID-19 ( 13 ). However, the mechanism of abatacept acting on COVID-19 remains unclear.…”