Convalescent COVID-19 monocytes exhibit altered steady-state gene expression and reduced TLR2, TLR4 and RIG-I induced cytokine expression

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, can induce trained immunity in monocytes. Trained immunity is the result of metabolic and epigenetic reprogramming of progenitor cells leading to an altered inflammatory response to subsequent activation. To investigate the monocyte response 3-6 months post SARS-CoV-2 infection, steady-state gene expression and innate immune receptor stimulation were investigated in monocytes from unvaccinated SARS-CoV-2 naïve individuals and convalescent COVID-19 participants. The differentially expressed genes (DEGs) identified were involved in the regulation of innate immune signalling pathways associated with anti-viral defence. COVID-19 participants who had experienced severe symptoms exhibited a larger number of DEGs than participants that had mild symptoms. Interestingly, genes encoding receptors that recognise SARS-CoV-2 RNA were downregulated. DDX58, encoding retinoic-acid inducible gene I (RIG-I), was downregulated which corresponded with a reduced response to RIG-I activation. Furthermore, toll-like receptor (TLR)1/2 and TLR4 activation also exhibited reduced cytokine secretion from convalescent COVID-19 monocytes. These data suggest that following SARS-CoV-2 infection, monocytes exhibit altered steady-state gene expression and reduced responsiveness to innate immune receptor activation. As both RIG-I and TLRs recognise components of SARS-CoV-2, this may lead to a moderated inflammatory response to SARS-CoV-2 reinfection in the months following the initial infection. [Abstract copyright: Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.]