COVID-19 News: Study Shows That Red Blood Cells Play A Role In Multi-Organ Spread of SARS-CoV-2

COVID-19 News: A new study led by researchers from Universidad de Buenos Aires-Argentina involving a MHV murine model has found that that red blood cells play a role in multi-organ spread of SARS-CoV-2.


 
COVID-19 is a complex disease that affects various organs beyond the respiratory system. While hematological disorders are commonly associated with the disease, the mechanism of SARS-CoV-2's multi-organ spread remains unclear.
 
To gain insights into this process, the study team analyzed the effects of a prototypical coronavirus in mice infected with murine hepatitis virus (MHV) and compared the findings with real-world data from COVID-19 patients.
 
The study team found viral RNA in not just the lungs but also the heart and kidneys of deceased COVID-19 patients.
 
In the MHV murine model, viral RNA and infectious particles were detected in multiple organs, including the liver, lung, brain, heart, kidney, spleen, pancreas, and even the blood.
 
Surprisingly, the researchers found that the virus hitchhiked on red blood cells (RBCs), with higher viral load levels detected in RBCs than in plasma. The infected mice had decreased RBC count, hematocrit, and hemoglobin levels. Treating the infected mice with hemin triggered more severe symptoms, but combining hemin treatment with chloroquine attenuated the infection and its clinical manifestations.
 
Computational docking suggested that heme could bind to the MHV Spike protein in a way similar to that observed for SARS-CoV-2.
 
The study findings suggest that the interaction of the virus with RBC hemoproteins plays a role in its multi-organ spread.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2023.03.29.23287591v1
 
The study team reported for the first time the presence of coronavirus genetic material and assess the infectious capacity of the virus in the blood compartment, specifically in plasma and red blood cells (RBCs).
 
This finding reveals the critical role of the blood compartment in viral dissemination. Additionally, the study findings describe a possible mechanism through which coronavirus may induce hemolysis, which involves sequestering heme and "hitchhiking" its way into multiple organs.
 
Using a docking experiment, the study team demonstrated that heme is capable of binding to the mouse hepatitis virus (MHV) Spike protein in a similar manner to that observed for SARS-CoV-2. This finding provides a plausible explanation for the enhanced infection observed in the in vivo model when heme is available. Moreover, chloroquine was found to impair the effects of hemin, a heme analog, thereby restoring blood parameters.
 
Hematological dysregulations, including leukopenia, thrombocytopenia, and coagulopathy, have been identified as common manifestations in severe COVID-19 patients. Among these, functional alterations in RBCs have been suggested as potential causes for long COVID.
 
The study team utilized the MHV preclinical model of coronavirus infection as an alternative model for studying COVID-19, as mice are the natural host of thi s virus. This model effectively replicates several key aspects of human coronavirus disease, including viral replication, pathology, and immune response. The study uncovered the multiple organ pleiotropy of the virus, in line with observations in human samples.
 
The study findings revealed some notable findings, such as minimal to null detection of viral presence in patient sera. One plausible explanation for the strong viral presence in plasma and RBCs observed in the preclinical model is that serum is depleted from fibrinogen and other clotting factors, which could be necessary scaffolds for the virus to attach to. Furthermore, plasma contains platelets, which have been shown to present several viral host receptors, which could partially explain the presence of viral particles in the plasma. This finding also highlights why the blood compartment was overlooked in earlier studies.
 
Interestingly, RBCs, platelets, and epithelial cells share other SARS-CoV-2 host cell receptors, such as CD147.
 
Numerous studies and past COVID-19 News coverages have reported abnormal RBC parameters in COVID-19 patients, indicating that the virus may be causing hemolysis. Consequently, various drugs and drug candidates targeting hemolysis have been suggested as protective strategies against severe COVID-19. It has been implied that host and viral proteins involved in SARS-CoV-2 infection differentially bind heme, which could significantly impact viral pathogenesis, particularly in the context of severe COVID-19.
 
Heme binds to viral proteins such as the Spike glycoprotein and protein 7a, as well as the host protein ACE2, emphasizing the importance of labile heme in preexisting or SARS-CoV-2-induced hemolytic conditions in COVID-19 patients.
 
In line with this, the study team’s computational docking analysis provides an accurate in silico model reflecting putative amino acids from the MHV Spike protein that can interact with heme, highlighting structural similarity with the complex formed by the SARS-CoV-2 Spike protein with heme and its metabolites.
 
Given that some reports have shown that COVID-19 patients with severe disease had higher levels of free heme compared with patients with mild disease, the study team inferred that viral infection could benefit from RBC lysis.
 
In order to test their hypothesis, the study team introduced hemin while infecting mice with MHV. Strikingly, results displayed a significant increase in viral RNA abundance in all assessed organs. However, this increase was not accompanied by a significant increase in infectious capacity. The reasons for this discrepancy may include viral latency, immune response, and the sensitivity of detection methods.
 
Although there was a discrepancy between viral genome and infectivity in the organs assessed in the in vivo model, both plasma and RBCs displayed increased presence of viral genome and particles when hemin was administered. Notably, like SARS-CoV-2, MHV-A59 does not express hemagglutinin esterase, suggesting that hemin is binding to other viral proteins. Overall, these results clearly indicate that heme provides a survival advantage for the virus.
 
The study team hypothesized that if hemin/heme was offering an evolutionary advantage for the virus to shuttle throughout the body, impairing its binding to heme would block viral spreading.
 
The study team reasoned that chloroquine (CQ) could counteract the hemin effect as it is well-known that CQ binds heme. CQ has been used for the treatment of malaria and many other conditions and has been previously reported to have antiviral effects against a broad range of viruses. In the context of drug repurposing, CQ emerged as a logical candidate for the treatment of COVID-19 patients and was widely used during the pandemic, albeit with much criticism.
 
CQ treatment has been linked to anticoagulant effects, preventing thrombosis and acute respiratory distress syndrome (ARDS), which are known COVID-19 consequences. However, several clinical trials assessing the safety and efficacy of CQ administration in COVID-19 patients concluded with controversial results. In light of our results, one might speculate that the blood compartment's association with this drug might have been disregarded.
 
In the preclinical model, the inclusion of CQ was not intended as a treatment but rather as a means to sequester hemin/heme, thereby halting heme availability and viral spreading. In line with this, the study findings showed that upon combined H+CQ treatment, viral RNA abundance decreased significantly in almost all organs. Interestingly, although infectious capacity did not quite accompany the viral RNA abundance reduction, the blood compartment was significantly impacted upon H+CQ treatment. Both viral genome and infectivity were significantly reduced by the combined H+CQ treatment in plasma and RBCs compared with MHV infection or MHV+H. Furthermore, blood parameters, including RBC, hematocrit (HCT), and hemoglobin (HGB), were improved in MHV+H+CQ compared with MHV infection alone or MHV+H.
 
This data clearly demonstrates that the availability of heme, either artificially supplemented or as a byproduct of hemolysis, and the binding to heme (demonstrated to bind Spike protein by our in silico model) may support an evolutionary advantage for the virus, favoring its immune escape.
 
In conclusion, the study findings have demonstrated for the first time that SARS-CoV-2 coronavirus multi-organ disease is accompanied by the binding of the coronavirus to RBCs. This discovery may have significant implications associated with blood abnormalities in active and recovered COVID-19 patients. If accurately surveyed, these findings could become critical biomarkers in determining disease progression and aiding in the development of therapeutics for patients with severe COVID-19.
 
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