Erythroid precursors and progenitors suppress adaptive immunity and get invaded by SARS-CoV-2

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread around the world. Although the vast majority of patients present with mild symptoms, about 15% of COVID-19 cases become severe and may end up in hospital or death. Several studies have documented that the severity and clinical outcomes are related to dysregulated antiviral immunity and enhanced and persistent systemic inflammation. However, what causes hypoxia remains largely unclear. Therefore, the question of whether SARS-CoV2 affects erythropoiesis, the process by which the body produces red blood cells, deserves an answer.

Intensive molecular research showed that SARS-CoV2 gains entry into the body using its spike-like glycoprotein (S protein) on its surface to bind to angiotensin-converting enzyme 2 (ACE2). The angiotensin-converting enzyme is a protein on the surfaces of most cells that generates small proteins that regulate cell functions. Studies also showed that besides binding to ACE2, SARS-CoV2 downregulates ACE2 cell surface expression and supresses its protective function.

The effect of SARS-CoV2 on erythropoiesis is still not clear. However, introductory models indicate that SARS-CoV2 could inhibit heme metabolism and trigger hemoglobin denaturation. Consequently, hemoglobin alteration will compromise blood’s oxygen-carrying capacity in Covid-19 patients leading to hypoxia. In addition, proteomic studies have confirmed ACE2 in red blood cells, implying that the SARS-CoV2 virus could target red blood cells.

Reduced red blood cells in the body due to SARS-CoV2 could stress erythropoiesis as a response to compensate for the reduced blood oxygen levels. Consequently, stress erythropoiesis will result in plenty of erythroid precursors in the blood. Erythroid precursors are the CD71⁺ erythroid cells co-expressing CD235a and CD71 in humans. They are cells in the erythroid series derived from myeloid progenitor cells that produce mature red blood cells. CD71⁺ erythroid cells have immunosuppressive and immunomodulatory properties and have been implicated in reduced innate immune responses. However, scientists are yet to explore whether SARS-CoV2 can target these cells.

In light of the above observations, Canadian researchers Shima Shahbaz, Lai Xu, Mohammed Osman, Wendy Sligl, Justin Shields, Michael Joyce, D. Lorne Tyrrell, Olaide Oyegbami, and led by Professor Shokrollah Elahi, from the University of Alberta sought to investigate the frequency and functionality of CD71⁺ erythroid cells in various Covid-19 patient groups. Their research work is published in the journal Stem Cell Reports.

The authors observed a considerable expansion of CD71⁺ erythroid cells in the peripheral blood of moderately and severely ill patients. The expansion was associated with the severity of the disease and ICU admissions. CD71⁺ erythroid cells from the Covid-19 patient groups considered in this study exhibited considerable arginase I/II and reactive oxygen species expression. These properties enabled the cells to exert global immunosuppression effects on thymus cells (T cells) and significantly impair cytokine production. The negative interconnection between the frequency of thymus cells and CD71⁺ erythroid cells percentages in the peripheral blood of the patients further reinforces these observations. In part, CD71⁺ erythroid cells pathological abundance explains the associated frequency and functionality changes of various immune cells in Covid-19 patients.

Consistent with previous studies, the authors reported low hemoglobin levels, particularly in severely-sick Covid-19 patients, and consequently, they expected to observe stress erythropoiesis. Their findings confirmed that low hemoglobin levels were associated with the elevated proportion of CD71⁺ erythroid cells in the blood.

The study findings also indicate the presence of a subset of CD71⁺ erythroid cells as CD71⁺, CD235a⁺, and CD45⁺ cells. They demonstrated that CD45⁺ CD71⁺ erythroid cells were the dominant ACE2/TMPRSS2-expressing cells. CD45⁺ CD71⁺ erythroid cells possessed the highest CD174/CD26 expression, yet another SARS-Cov2 receptor. Put together; these observations suggest that CD71⁺ erythroid cells are attractive SARS-CoV2 targets. Therefore, the infectivity of red blood cells progenitors explains the observed hypoxia in Covid-19 patients. The high CD71⁺ erythroid cells percentages in severely ill patients suggest stress hematopoiesis.

Dexamethasone was shown in clinical trials to have a clear benefit in patients with COVID-19 on mechanical ventilation or oxygen alone at the time of randomization. Based on the positive results the World Health Organization recommended the use of dexamethasone in treating critically ill patients with COVID-19. However, understanding dexamethasone’s mode of action merits the uppermost importance. Dexamethasone seems in addition to its anti-inflammatory function can also influence hematopoiesis, and promotes erythroid cells maturation. Using elegant molecular experimental studies, Professor Elahi and the research team demonstrated that dexamethasone may exert it pharmacological effect by suppressing the response of the ACE2 and TMPRSS2 receptors to SARS-CoV-2 which reduce the likelihood of infection and also through promoting CD71⁺ erythroid cells maturation. These two pharmacological mechanisms may explain why dexamethasone significantly reduce the risk of SARS-CoV-2 infection severity.

The new study provides in depth understanding the clinical symptoms of severe COVID-19 patients in particular the impact of SARS-CoV-2 infection on hypoxia and erythropoiesis observed in Covid-19 patients.