The COVID-19 pandemic continues to constitute a huge threat to public health worldwide and despite the efforts and advances to untangle the mechanisms of SARS-CoV-2 infection and transmission among humans, we are still blind to the overall COVID-19 pathology and its consequences.

The results presented in this paper might help understand the emergent erythropoiesis and aberrant presence of erythroid progenitors in the peripheral blood of severe COVID-19 patients. These recent evidences indicate that the increase of erythroid progenitors in circulation constitute a hallmark of both severity and fatality in COVID-19 patients.

In this context, observations that the virus can be detected after 14 days in the ERP-S2 without impairing their viability, rather causing an increase of colonies, suggest that the expansion of circulating erythroid cells that have been reported in severe patients may be due to direct infection of upstream CD71+CD235a- progenitors.

In depth research will be key to elucidate which of these two events, direct infection of erythroid progenitors and pathological increase of these
populations in the bloodstream, occur first in vivo in patients.

These results also open the question about the causality between direct SARS-CoV-2 infection of erythroid progenitors and clinical manifestations resulting from hemoglobin decline and anemia. In light of these findings, cannot be discarded the possibility that these symptoms are not simply a byproduct of inflammation and overall poor health and that, instead, direct infection of erythroid progenitors by SARS-CoV-2 contributes to this aberrant erythropoiesis.

The results constitute the first evidence of direct infection of specific erythroid progenitors, named as ERP-S2 (CD71+CD235A-) and ERP-S3 (CD71+CD235a+), by SARSCoV-2. Especially relevant is the high ability (or facility) of the virus to infect ERP-S2, the most vulnerable erythroid progenitor population.

Based previous works and observations, ERP-S2 population includes colony forming units-erythroid (CFU-E) cells and early pro-erythroblast cells. Considering their high proliferative capacity, the infection of these progenitors by SARS-CoV-2 may have a major detrimental impact not only in erythropoiesis, but also in the spread of the virus through millions of circulating infected cells. Also, this presents a scenario in which infected
erythroid progenitors may cause local inflammation in the bone marrow, which could cause a drastic disruption of hematopoiesis and the production of immune cells.

In contrast to the observations in erythroid progenitors, bone marrow HSPCs(CD34+CD38-) do not express ACE2 and TMPRSS2 at the RNA or protein level. Consequently, HSPCs are not infected by SARS-CoV-2.

In this report, are also provided clinical data of a cohort of 30 COVID-19 patients that were treated in intensive care units (ICU) at King’s College London: the decline in hemoglobin levels coincides with an aberrant increase of nucleated red blood cells in circulation. These nucleated red blood cells correspond to ERP-S3 cells, population that can be infected by SARS-CoV-2 and the infection induces the immunosuppressive capacity of these cells.

Importantly, these results might also have an impact in understanding of the transmission and incubation period of SARS-CoV-2, as different levels of infected progenitors in the bloodstream could greatly alter such parameters.

Finally, identification of infected ERP-S2 populations in hospitalized patients could help identify those patients that will suffer from severe hematopathology, potentially allowing pre-emptive management strategies to improve outcomes.