Mild SARS-CoV-2 Infections Causes Transcriptional Reprogramming Of The Host’s CD14+ Monocytes Resulting In Dysfunctional Monocytes

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A new study by researchers from Imperial College London-UK, Wellcome Sanger Institute-UK and Aix Marseille Université-France has found that even mild and moderate SARS-CoV-2 infections causes transcriptional reprogramming of the host’s CD14+ monocytes.

The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.04.03.486830v1

COVID-19 is a respiratory tract infection caused by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). In unvaccinated individuals, the majority of infections are mild or asymptomatic, but 15% of patients develop moderate to severe disease requiring hospitalisation, and 5% develop critical disease with life-threatening pneumonia, acute respiratory distress syndrome (ARDs) and septic shock1.

During the acute phase of infection, myeloid cells including monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and play a major role in the pathogenicity of the disease2,3.

Moreover, contrasting observations regarding the development of cytokine storms vs. immunosuppression 4,5 and the overactive or deficient type I IFN response in the lungs and in peripheral blood6-11 have been described for the role of myeloid cells in COVID-1912.

Despite these apparent contrasting works, most studies have observed dysregulated innate immune responses and reduced expression of human leukocyte antigen DR isotype (HLA-DR) by circulating myeloid cells, which is considered a marker of immune suppression10,13-17.

Monocytes are blood-circulating, phagocytic, innate immune leukocytes with important functions in pathogen sensing, and innate and adaptive immune response activation during viral infection18. Despite their heterogeneity19, monocytes are broadly classified into three subsets based on the expression of CD14 and CD16 into classical (CD14+CD16-), intermediate (CD14+CD16+), and nonclassical (CD14lowCD16+) monocytes18.

During viral infection, circulating monocytes infiltrate affected tissues and differentiate into inflammatory macrophages and dendritic cells (DCs)20, contributing to pathogen clearance and tissue regeneration.

Here we deeply examined the phenotype and functionality of the main monocyte population in humans, i.e. classical CD14+ monocytes, in patients with COVID-19 and compared them to those of healthy individuals.

We found that ex vivo isolated CD14+ monocytes from mild and moderate COVID-19 patients are phenotypically different from monocytes from healthy individuals, displaying differential expression of costimulatory receptors and MHC molecules, epigenetic alterations and a dysfunctional metabolic profile that is accompanied by decreased ex vivo NFκB activation, while maintaining an intact type I IFN antiviral response.

Subsequent pathogen sensing ex vivo led to a state of functional unresponsiveness that correlated transcriptionally with that of a endotoxin-induced tolerance signature. Moreover, monocytes switched their gene expression signature from canonical innate immune functions to a pro-thrombotic phenotype characterized by increased expression of pathways involved in immunothrombosis.

In response to SARS-CoV-2 or other viral or bacterial components, monocytes displayed decreased expression of type I IFN responses, decreased pro-inflammatory cytokine production and costimulatory receptor expression and defects in the epigenetic remodelling and metabolic reprogramming that usually occurs upon pathogen sensing.

These results provide a potential mechanism by which innate immune dysfunction in COVID-19 contributes to disease progression and identifies potential therapeutic targets.

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