SARS-CoV-2 News: Study Shows That Release Of Immature Blood Cells From Bone Marrow Signifies COVID-19 Severity
: A new study involving physicians and researchers from Kiel University, the University Medical Center Schleswig-Holstein (UKSH) and the Universities of Bonn, Cologne, Luebeck, Tuebingen and Nijmegen as well as the Research Center Borstel-Leibniz Lung Center and the German Centre for Neurodegenerative Disorders (DZNE) have demonstrated that not only classic immune cells play a role but in particular, the release of immature precursor cells from the bone marrow into the blood indicates a particularly severe course of the disease and could contribute to complications.
According to the study team, the temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is required for understanding skewed immune responses and finding outcome predictors.
In this research, the study performed a longitudinal multi-omics study utilizing a two-centre cohort of 14 patients. The study team analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients.
Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, the team also identified an expansion of IFN-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling.
Significantly, megakaryocyte- and erythroid cell-derived co-expression modules were also predictive of fatal disease outcome.
The study findings demonstrate the broad cellular effects of SARS-CoV-2 infection beyond classical immune cells and may serve as an entry point to develop biomarkers and targeted treatments of patients with COVID-19.
The study findings were published in the peer reviewed journal: Immunity https://www.sciencedirect.com/science/article/pii/S1074761320305045
It has been found that Infections with the novel coronavirus SARS-CoV2 may result in highly heterogeneous clinical pictures. While many of the infections are mild or even asymptomatic, the disease can become life-threatening, especially in older people.
Typically in these severe cases, other organs such as the heart or kidneys can be affected in addition to the lung. An immunological misfiring plays an important role, but findings are accumulating that damage to small blood vessels and over-activated blood clotting are decisive factors for a severe course. One of the most common direct causes of death from COVID-19 is blood clots in the lungs.
Lead authors of the study, Professor Dr Philip Rosenstiel, Director of the Institute for Clinical Molecular Biology (IKMB) at Kiel University and UKSH explained to Thailand Medical News, "Despite numerous studies, we actually know relatively little about the course of the disease over time. Which cell types&n
bsp;play an important role here and when? And can we identify early molecular signatures in the blood that point to severe course of the disease later on? These were questions we asked ourselves at the beginning and we got surprising answers."
The study team examined blood samples from COVID-19 patients who were hospitalized at the university hospitals in Kiel, Bonn, Cologne and Nijmegen.
In a group of 14 patients, circulating blood cells were analyzed in a time series. Blood samples from healthy people were used as a comparison.
Dr Joana Pimenta Bernardes, a postdoc scientists at Kiel University the who is one of the first authors of the study together with the other two young researchers added, "The special feature is that we were able to analyze hundreds of thousands of cells in parallel with the help of so-called single cell genomics and were thus able to identify rare cell types."
"Together with other data such as clinical laboratory values and measurements of inflammatory messengers, we were able to create a kind of fingerprint, a signature, of the altered functioning of these cells and track it over time," explained Dr Florian Tran, Clinician Scientist and Dr Neha Mishra, who are both also researching at the IKMB.
Importantly, the signatures of two immature cell types are therefore particularly characteristic of severe COVID-19 disease: platelet precursor cells, so-called megakaryocytes, and immature red blood cells.
Dr Tran further explained, "This is particularly surprising because these precursor cells are normally not in the blood but in the bone marrow, where they mature as needed. We know of such progenitor cells being washed out into the blood of seriously ill patients, for example in bacterial sepsis (blood poisoning). This has not yet been described for COVID-19.”
Dr Joachim Schultze, professor at the University of Bonn and research group leader at the DZNE, one of the last authors of the study added, "With the help of high-precision cellular genomic analyses, we were able to draw a very detailed picture of the cellular changes throughout the course of the disease. While previously we mainly looked at immune cells, we were now able to find cell types that had previously been overlooked."
The study team gained important insights from a group of 39 COVID-19 patients who had been treated in the intensive care unit in Nijmegen, i.e. had particularly severe courses of disease. In this group of patients, a signature of the megakaryocytes and red blood cell progenitor cells was particularly strong in patients who died of the disease compared to patients who recovered.
Dr Rosenstiel added, "The megakaryocytes reflect a well-known COVID-19 problem: blood platelets are responsible for blood coagulation. One of the most common direct causes of death from COVID-19 is coagulation problems. The emergency-activated megakaryocytes in the blood may produce platelets that aggregate more easily and thus lead to the coagulation problems."
The increase in red blood cell progenitor cells indicates a lack of oxygen and is known as an emergency reaction in severe lung diseases.
The detailed research has been made possible by the nationwide consortium ie the "German COVID-19 OMICS Initiative" (DeCOI) and was carried out in cooperation with partners from the "Human Cell Atlas," an international consortium for single cell analysis.
Dr Schultze, who is also the coordinator of the DeCOI consortium said, "It was only through this teamwork that the complex analyses and interpretation of the data could be mastered in the short time available. With the present work, we have now created the basis for validating novel biomarkers at an early stage of COVID-19 disease to identify patients at risk for a severe course of the disease. This would enable us to improve the care of particularly severely affected patients even more specifically."
The study team concluded, “Together, the results indicate a profound reaction of the erythroid lineage to COVID-19 at different phases of the disease. These features of the computed disease trajectory were linked to clinical outcome in a larger retrospective cohort of 39 mechanically ventilated COVID-19 patients. We could show that two modules from cohort 1, M4 (related to MK numbers in cohort 1) and M7 (indicative of erythropoiesis in cohort 1), were significantly correlated with a fatal outcome in the independent cohort. Decrease in expression of the M2 module (associated with hypomorphic type I IFN in cohort 1) in a broad array of cell types including monocytes, NK cells, CD8+ T cells and PBs was present in both survivors and non-survivors, corroborating the observation of failing type I IFN in severe COVID-19, but questioning its clear relation to fatal outcome. The study findings clearly suggest that regulatory events in megakaryocytic and erythroid cells may act as pivotal components of an unfavorable course of COVID-19, which mandates further prospective exploration.”
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