Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.

Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2-infected cells

“…Second, patients with severe diseases exhibit reduced circulating pDCs and low plasma IFN-I/λ levels when compared to mild COVID-19 patients 7,19,20 . Third, IL-3, which increases innate immunity likely by promoting the recruitment of circulating pDCs into the airways, is reduced in the plasma of patients with high viral load and severity/mortality 71 . This evidence highlights that several biomarkers of IFN-I/λ response are diminished in COVID-19 patients, and hereby points to pDCs as a primary candidate in the progression of COVID-19.…”

IFN-γ Induces PD-L1 Expression in Primed Human Basophils

“…IL-3 acts as a hematopoietic growth factor. A recent study has confirmed the protective role of IL-3 and its potential use as a predictive marker in severe SARS-CoV-2 infections [ 49 ]. Of note, our data show that IL-3 is indispensable for IFN-γ-induced PD-L1 expression in basophils.…”

“…Of note, our data show that IL-3 is indispensable for IFN-γ-induced PD-L1 expression in basophils. Severe COVID-19 patients display low IL-3 in the circulation [ 49 ] that could be responsible for the reduced expression of PD-L1 in basophils reported in one study [ 6 ]. In addition, the reduced IL-3 would also affect the survival of basophils and their ability to support protective IgG responses [ 50 ].…”

Genetic polymorphisms affecting nitric oxide and β-cytokine pathways may contribute to increased COVID-19 mortality in schizophrenia

“…Genetic polymorphisms in all three components of the IL-3 signaling pathway, CSF2RB (coding for the βc Receptor (βcR)), IL-3, and IL- 3 Receptor α (IL-3Rα) genes, are potentially able to directly change gene expressions and have been reported in SCZ ( Chen et al, 2008 ; Chen et al, 2007 ). IL-3 activity may be lower in SCZ patients while impaired IL-3 function is associated with increased disease severity as well as increased viral load and mortality in SARS-CoV-2 infected patients ( Benard et al, 2021 ; Chen et al, 2008 ).…”