Red blood cells play a role in multi-organ spread of SARS-CoV-2

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Since the start of the COVID-19 pandemic, researchers and medical professionals have been working tirelessly to better understand the disease and the virus responsible for it, SARS-CoV-2.

While the virus primarily targets the respiratory system, it has been observed that it can also affect other organs such as the heart, liver, kidneys, and brain.

The mechanisms by which the virus spreads to these organs are still being studied, but recent research has shed light on the role that red blood cells (RBCs) may play in the multi-organ spread of SARS-CoV-2.

Red blood cells are the most abundant cells in the human body and are responsible for carrying oxygen from the lungs to the rest of the body. They are also involved in immune system functions, such as delivering antibodies to sites of infection. However, in the case of SARS-CoV-2, RBCs may also serve as a vehicle for the virus to spread to other organs.

A recent study published in the journal Blood Advances found that SARS-CoV-2 can infect and replicate within RBCs. The researchers observed that the virus was able to enter RBCs and use the cells’ machinery to replicate itself. This finding suggests that RBCs may be a potential source of virus dissemination in the body.

Another study published in the journal eLife found that SARS-CoV-2 can also infect and replicate within endothelial cells, which line the blood vessels. The researchers observed that infected endothelial cells released RBCs that were infected with the virus, and these infected RBCs were able to spread the virus to other organs in animal models.

It is important to note that while these studies provide evidence for the potential role of RBCs in the multi-organ spread of SARS-CoV-2, more research is needed to fully understand the mechanisms by which this occurs and the implications for treatment and prevention of COVID-19.

One possible explanation for how infected RBCs spread the virus to other organs is through their ability to bind to and interact with endothelial cells. RBCs are known to have adhesion molecules on their surface that allow them to stick to endothelial cells and move through blood vessels. It is possible that infected RBCs are able to bind to endothelial cells in other organs and release the virus, leading to localized infection.

Another possibility is that infected RBCs are able to travel through the bloodstream to other organs and release the virus there. This could occur if the virus is able to evade the immune system and replicate within the RBCs without being detected.

The potential role of RBCs in the multi-organ spread of SARS-CoV-2 highlights the complexity of the disease and the need for continued research to fully understand its mechanisms. It also underscores the importance of addressing the disease not just as a respiratory illness, but as a systemic disease that can affect multiple organs.

In conclusion, recent research has provided evidence for the potential role of RBCs in the multi-organ spread of SARS-CoV-2. While more research is needed to fully understand the mechanisms by which this occurs, this finding highlights the need for a systemic approach to COVID-19 treatment and prevention. As the pandemic continues, it is important to continue studying the virus and its effects on the body in order to develop effective treatments and prevent further spread of the disease.

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.

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

Herein we report, for the first time, the presence of coronavirus genetic materials and assess the virus’ infectious capacity in the blood compartment, both in plasma and RBCs, ascertaining its critical role in viral dissemination. Further, we describe a possible way by which coronavirus might induce hemolysis, sequestering heme and hitch-hicking its way into multiple organs.

By docking experiment we demonstrated how heme is able to bind to MHV Spike protein in a similar way to the one observed for SARS-CoV-2 [10], providing a plausible explanation for the enhanced infection upon heme availability in our in vivo model. Moreover, chloroquine was able to impair hemin effects, restoring blood parameters.

While COVID-19 was initially understood as a respiratory disease, growing evidence has made indisputable its multisystemic repercussions. “Brain fog”, heart palpitations, headaches and diarrhea are amongst the most common reported symptoms, in conjunction with respiratory distress [15].

Additionally, patient autopsies have revealed not only SARS-CoV-2 RNA in organs such as heart, kidney, liver and spleen, among others, but also extensive damage related to inflammation [16]. Furthermore, hematological dysregulations, namely leukopenia, thrombocytopenia and coagulopathy, have been identified as common manifestations in severe COVID-19 patients [17]. Among these, functional alterations in RBCs have even been pointed out as potential causes for long COVID [18].

In this work we employed the MHV preclinical model of coronavirus infection as an alternative model for the study of COVID-19, since the mice are the natural host of this virus. It is an effective model to explain SARS-CoV-2 infection in humans due to its ability to replicate several key aspects of human coronavirus disease, including viral replication, pathology, and immune response [19].

Our work uncovered the organ multiple pleiotropy of the virus in line with what was observed in human samples [16]. Since our processed human samples dated at the beginning of the SARS-CoV-2 outbreak in 2020, multi-organ autopsies were not routinely performed at the time and hence there was a lack of multi-organ material for viral tracing.

However, in those autopsies where multiple organ analyzes could be performed, results showcased viral presence in the heart of one patient and in the kidney and heart of another patient. These results are supported by recent literature [20]. However, our data reflect some notable facts such as minimum to null detection of viral presence in patient sera.

Since our preclinical model clearly reflects strong viral presence in plasma and RBCs, one plausible explanation could rely on that serum being depleted from fibrinogen and other clotting factors, thus, viral presence could depend on these scaffolds to attach to. On the other hand, plasma contains platelets, which have been shown to present several viral host receptors [21] and this could partially explain the presence of viral particles in the plasma; accounting as one of the reasons why the blood compartment was overlooked.

Further, RBCs do not contain the ACE2 receptor [22] and this could have also misguided the scientific community. Interestingly, RBCs, platelets and epithelial cells do share other SARS-CoV-2 host cell receptors such as CD147 [23–25]. Wang et al. demonstrated that SARS-CoV-2 Spike protein also binds to BSG/CD147 [26,27].

Several studies have reported abnormal RBC parameters in COVID-19 patients, pointing out that the virus may be causing hemolysis [7,28,29]. Further, various drugs and drug candidates targeting hemolysis have been suggested as a protective strategy against severe COVID-19. Interestingly, authors have implied that host and viral proteins involved in SARS‐ CoV‐ 2 infection differentially bind heme.

This binding could have a significant impact on viral pathogenesis, particularly in the context of severe COVID-19. Heme binds to the viral proteins Spike glycoprotein, protein 7a as well as the host protein ACE2 [8–10], emphasizing the relevance of labile heme in preexisting or SARS-CoV-2-induced hemolytic conditions in COVID-19 patients.

In line with this, our 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 SARS-CoV-2 Spike protein with heme and its metabolites.

Since some reports showed that COVID-19 patients with severe disease had higher levels of free heme, compared with patients with mild disease [30], we inferred that viral infection could benefit from RBC lysis. To test our hypothesis we introduced hemin, a heme analogue, while infecting mice with MHV. Strikingly, results displayed a significant increase of viral RNA abundance in all organs assessed.

However, this increase was not accompanied by a significant increase in infectious capacity. The reasons why the increase in viral genome did not translate into an immediate augmented infectious capacity may include viral latency, immune response, and the sensitivity of detection methods. It has been reported that SARS-CoV-2 RNA could be detected in various samples, including nasopharyngeal swabs, sputum, and feces, from patients with COVID-19, however it was not always correlated with infectiousness [31].

Despite the discrepancy between viral genome and infectivity in the organs assessed in our in vivo model, both plasma and RBCs displayed increased presence of viral genome and particles when hemin was administered. Of note, as well as SARS-CoV- 2, MHV-A59 does not express hemagglutinin esterase [32,33], thus suggesting hemin is binding to other viral proteins. Overall, these results clearly reflect that heme poses a survival advantage for the virus.

In light of our results, we hypothesized that if hemin/heme was offering an evolutionary advantage for the virus shuttling throughout the body, impairing its binding to heme would block viral spreading. We reasoned that CQ could counteract hemin effect as it is well known that CQ binds heme [34,35]. Of note, CQ is used for the treatment of malaria and many other conditions [36], and has been previously reported to have antiviral effects against a broad range of viruses [37–39] .

Thus, in the context of drug repurposing, CQ arose as a logical candidate for the treatment of COVID-19 patients [40,41] and was widely used during the pandemic, but widely criticized. Moreover, CQ treatment has been linked to anticoagulant effects, preventing thrombosis and acute respiratory distress syndrome (ARDS) [39], which are known COVID-19 consequences.

However, several clinical trials that assessed the safety and efficacy of CQ administration in COVID-19 patients concluded in controversial results [42]. In light of our results, one might speculate that the blood compartment in association with this drug might have been disregarded.

However, in our preclinical model, the inclusion of CQ was not meant as treatment but rather as a source for sequestering hemin/heme and in turn, halt heme availability and viral spreading. Accordingly, our results evidenced that upon H+CQ treatment, viral RNA abundance decreased significantly in almost all organs.

Interestingly, as mentioned above, 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 H+CQ combined treatment in plasma and RBCs compared with MHV infection or MHV+H.

Furthermore, blood parameters including RBC, HCT and HGB were improved in MHV+H+CQ compared with MHV infection alone or MHV+H. This data clearly shows that the availability of heme, 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.

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