Transcriptional reprogramming from innate immune functions to a pro-thrombotic signature by monocytes in COVID-19

Abstract

Although alterations in myeloid cells have been observed in COVID-19, the specific underlying mechanisms are not completely understood. Here, we examine the function of classical CD14+ monocytes in patients with mild and moderate COVID-19 during the acute phase of infection and in healthy individuals. Monocytes from COVID-19 patients display altered expression of cell surface receptors and a dysfunctional metabolic profile that distinguish them from healthy monocytes. Secondary pathogen sensing ex vivo leads to defects in pro-inflammatory cytokine and type-I IFN production in moderate COVID-19 cases, together with defects in glycolysis. COVID-19 monocytes switch their gene expression profile from canonical innate immune to pro-thrombotic signatures and are functionally pro-thrombotic, both at baseline and following ex vivo stimulation with SARS-CoV-2. Transcriptionally, COVID-19 monocytes are characterized by enrichment of pathways involved in hemostasis, immunothrombosis, platelet aggregation and other accessory pathways to platelet activation and clot formation. These results identify a potential mechanism by which monocyte dysfunction may contribute to COVID-19 pathology.

Spatiotemporal analysis of SARS-CoV-2 infection reveals an expansive wave of monocyte-derived macrophages associated with vascular damage and virus clearance in hamster lungs

“…This confirms that the hamster model is also suitable to further analyse the pathomechanisms related to blood clotting. It remains to be verified if the MDM also change their transcriptional profile to a pro-thrombotic signature, similar to that reported in COVID-19 in humans [48]. Taken together, our observations suggest that the vascular hyperpermeability serves as trigger for MDM entry into the tissue and the areas of vascular damage may define the sites of massive MDM infiltration.…”

Long COVID: pathophysiological factors and abnormalities of coagulation

“…] fueled by proinflammatory molecules [ 165 ]. In summary, chronic systemic inflammation may alter the hemostatic balance to a prothrombotic state [ 169 ].…”

Innate and Adaptive Immunity during SARS-CoV-2 Infection: Biomolecular Cellular Markers and Mechanisms

“…Since the advent of FACS and discovery of monocytes by Ehrlich and Metchnikoff, currently identified monocyte subsets are broadly defined by classical (CD14 hi/+ , CD16 − ), intermediate (CD14 hi/+ , CD16 lo/+ ), and non-classical (CD14 −/lo , CD16 + ) markers [ 203 , 206 , 207 ]. Monocytes represent around 10% of the leukocyte population, and they are short-lived (1–2 days) while circulating in blood, bone marrow, and spleen (see Figure 4 ).…”

“…Analysis also, remarkably, illustrated that IL-8 (CXCL8) and IL-1β together with CCL3 were substantially upregulated without induction of pro-inflammatory cytokine genes such as TNF, IL-6, IL-1, CCL3, CCL4, or CXCL2 in the cells that possessed reduced HLA-DR expression and reduced antigen presentation capability [ 223 ]. On the other hand, more recently, in a SARS-CoV-2 case control study (n = 37), it has been clarified that there was an initial increase in classical monocytes (CD14 hi/+ , CD16 −− ) with a decrease in intermediate (CD14 hi/+ , CD16 lo/+ ) and a gradual normalization of non-classical monocytes (CD14 −/lo , CD16 + ) 6–7 months after follow-up, with changes to other cell subtypes below [ 203 , 204 , 207 , 224 ].…”

“…However, Mϕ subpopulations are further characterized by HLA-DR, CD195 (CCR5), and TNFR1/TNFR2 expression, which is also higher on intermediate monocytes, followed by classical and then non-classical monocytes as well as Mϕ [ 251 ]. A recent preprint suggests that, within acute SARS-CoV-2 infection, monocytes change IGS from innate immune functions as CD14 + monocytes develop into pro-thrombotic, showing differential upregulation of MHC II alongside MHC I downregulation (HLA-DR/HLA-ABC), with accompanying gene signatures downregulated that would affect IFN production (e.g., IFNA1, IFNA2), but also TLR7 and AIM2, affecting increased expression of pathways involved in hemostasis and immunothrombosis [ 207 ]. In contrast, TNFR2 is expressed at high levels on non-classical monocytes, followed by intermediate, and then the lowest expression was of classical monocytes [ 252 ].…”