Differential Impact of SARS-CoV-2 Isolates, Namely, the Wuhan Strain, Delta, and Omicron Variants on Erythropoiesis

Abstract

SARS-CoV-2 variants exhibit different viral transmissibility and disease severity. However, their impact on erythropoiesis has not been investigated. Here, we show SARS-CoV-2 variants differentially affect erythropoiesis. This is illustrated by the abundance of CD71⁺ erythroid cells (CECs) in the blood circulation of COVID-19 patients infected with the original Wuhan strain followed by the Delta and Omicron variants. We observed the CD45⁺CECs are the dominant subpopulation of CECs expressing the receptor, ACE2, and coreceptor, TMPRSS2, and thus, can be targeted by SARS-CoV-2. Also, we found CECs exhibit immunosuppressive properties, specifically CD45⁺CECs are the dominant immunosuppressive cells and via reactive oxygen species (ROS) and arginase I expression can impair CD8⁺ T cell functions. In agreement, we observed CECs suppress CD8⁺ T cell effector (e.g., Granzyme B expression and degranulation capacity [CD107]), which was partially but significantly reversed with l-arginine supplementation. In light of the enriched frequency of CECs, in particular, CD45⁺CECs in patients infected with the original (Wuhan) strain, we believe this strain has a more prominent impact on hematopoiesis compared with the Delta and Omicron variants. Therefore, our study provides an important insight into the differential impact of SARS-CoV-2 variants on erythropoiesis in COVID-19 patients. IMPORTANCE Silent hypoxia has been the hallmark of SARS-CoV-2 infection. Red blood cells (RBCs) work as gas cargo delivering oxygen to different tissues. However, their immature counterparts reside in the bone marrow and normally absent in the blood circulation. We show SARS-CoV-2 infection is associated with the emergence of immature RBCs so called CD71⁺ erythroid cells (CECs) in the blood. In particular, we found these cells were more prevalent in the blood of those infected with the SARS-CoV-2 original strain (Wuhan) followed by the Delta and Omicron variants. This suggests SARS-CoV-2 directly or indirectly impacts RBC production. In agreement, we observed immature RBCs express the receptor (ACE2) and coreceptor (TMPRSS2) for SARS-CoV-2. CECs suppress T cells functions (e.g., Granzyme B and degranulation capacity) in vitro. Therefore, our study provides a novel insight into the differential impact of SARS-CoV-2 variants on erythropoiesis and subsequently the hypoxia commonly observed in COVID-19 patients.

Keywords: Delta; Omicron; SARS-CoV-2; SARS-CoV-2 variants; Wuhan; erythropoiesis.

FIG 1

The frequency of CD71⁺ erythroid cells (CECs) resemble differential effects of SARS-CoV-2 variants on hematopoiesis. (A) Representative flow cytometry plots, and (B) cumulative data of the frequency of CECs in the peripheral blood mononuclear cells (PBMCs) of healthy controls (HC) and infected individuals with the Wuhan strain, delta, and Omicron variants. (C) Representative flow cytometry plots, and (D) cumulative data of the proportion of CD45⁻ and CD45⁺CECs in PBMCs of infected individuals with different SARS-CoV-2 isolated. (E) Representative flow cytometry plots, and (F) cumulative data of the percentages of ACE2 expressing CECs among CD45⁻ and CD45⁺ subpopulations of CECs in patients infected with the Wuhan strain. (G) Representative flow cytometry plots, and (H) cumulative data of the percentages of TMPRSS2 expressing CECs among CD45⁻ and CD45⁺ subpopulations of CECs in patients infected with the Wuhan strain. (I) Representative flow cytometry plots, and (J) cumulative results of the percentages of ACE2 expressing CECs among CD45⁻ and CD45⁺ subpopulations of CECs in patients infected with the Omicron variant. (K) Representative flow cytometry plots, and (L) cumulative results of the percentages of TMPRSS2 expressing CECs among CD45⁻ and CD45⁺ subpopulations of CECs in patients infected with the Omicron variant. Each dot represents data from an individual patient or study subject.

FIG 2

CD45⁺CECs in COVID-19 patients are more potent. (A) Representative flow cytometry plots of the gating strategy for CD45⁻ and CD45⁺CECs, and the expression of ROS and arginase I in CD45⁻ versus CD45⁺CECs. (B) Cumulative data of the intensity of ROS expression measured by mean fluorescence intensity (MFI) in CD45⁻ versus CD45⁺CECs. (C) Cumulative data of the intensity (MFI) of arginase I expression in CD45⁻ versus CD45⁺CECs. (D) Representative flow cytometry plots, and (E) cumulative data showing % CD8⁺ T cells expressing GzmB, or (F) CD107a without stimulation (unstim) or stimulated (stim) with anti-CD3/CD28 antibodies in the absence of CECs (−CECs) or presence (+CECs) without and with l-arginine supplementation (2 mM). (G) Cumulative data showing % CD8⁺ T cells expressing GzmB, or (H) CD107a without stimulation (Unstim) or stimulated (stim) with anti-CD3/CD28 antibodies in the absence of CECs (−CECs) or presence (+CECs). Each dot represents data from a human subject.