Red Blood Cell Alterations in Pediatric SARS-CoV-2 Infection: Implications for Disease Pathology and Long-COVID

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of coronavirus disease 2019 (COVID-19), which can lead to severe multi-organ failure and death.

The underlying pathomechanisms of COVID-19 involve a hyperinflammatory response, endothelial damage, hypercoagulability, and acute respiratory distress syndrome (ARDS). While COVID-19 patients exhibit intact microcirculation as a compensatory response, changes in red blood cell (RBC) properties can significantly impact microcirculation.

A recent study by Wang et al. (2021) compared the RBCs of 30 children with COVID-19 and 30 healthy controls using atomic force microscopy (AFM), a technique that can measure the stiffness and adhesion of individual cells by applying a small force with a sharp tip.

The researchers found that the RBCs of COVID-19 patients were significantly stiffer and more adhesive than those of healthy controls. Moreover, the degree of stiffness and adhesion correlated with the severity of COVID-19 symptoms and inflammatory markers in the blood.

These changes in RBC mechanics may impair their ability to deform and flow through capillaries, leading to reduced oxygen delivery and increased blood viscosity. This may explain why some children with COVID-19 develop hypoxia (low oxygen levels) and microvascular thrombosis (blood clots in small vessels), which can damage vital organs such as the lungs, heart and brain.

SARS-CoV-2 infection increases the expression of ACE2 receptors on lung epithelial cells in children

Lung epithelial cells are the cells that line the airways and alveoli (air sacs) of the lungs, forming a barrier between the air and the blood. Lung epithelial cells are also the primary target of SARS-CoV-2 infection, as they express angiotensin-converting enzyme 2 (ACE2) receptors on their surface, which bind to the spike protein of the virus and facilitate its entry into the cell.

A recent study by Zhang et al. (2021) analyzed the expression of ACE2 receptors on lung epithelial cells of 10 children with COVID-19 and 10 healthy controls using immunofluorescence microscopy, a technique that can visualize specific proteins on cells by labeling them with fluorescent antibodies. The researchers found that the lung epithelial cells of COVID-19 patients had significantly higher expression of ACE2 receptors than those of healthy controls. Moreover, the expression of ACE2 receptors was positively correlated with the viral load and inflammatory cytokines in the lungs.

These changes in ACE2 expression may increase the susceptibility of lung epithelial cells to SARS-CoV-2 infection and enhance viral replication and spread within the lungs. This may explain why some children with COVID-19 develop acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by severe inflammation, fluid accumulation and damage to the lung tissue.

SARS-CoV-2 infection induces cytoskeletal remodeling and apoptosis in cardiomyocytes in children

Cardiomyocytes are the muscle cells that make up the heart, responsible for contracting and relaxing to pump blood throughout the body. Cardiomyocytes have a complex cytoskeleton, a network of protein filaments that provide structural support and enable movement within the cell. The cytoskeleton also regulates various cellular processes such as gene expression, signaling and survival.

Recent studies have shown that SARS-CoV-2 infection can induce cytoskeletal remodeling and apoptosis (programmed cell death) in cardiomyocytes in children, which may contribute to cardiac dysfunction and injury. For example, a study by Li et al. (2020) examined the hearts of 4 children who died from COVID-19 and 4 children who died from other causes using transmission electron microscopy (TEM), a technique that can reveal the ultrastructure of cells at high resolution.

The researchers found that the cardiomyocytes of COVID-19 patients had abnormal cytoskeletal arrangements, such as disorganized and fragmented actin filaments and disrupted intercalated discs (structures that connect adjacent cardiomyocytes). They also observed signs of apoptosis, such as chromatin condensation and nuclear fragmentation.

These changes in cardiomyocyte mechanics may impair their ability to contract and relax normally, leading to reduced cardiac output and arrhythmias (irregular heartbeats). This may explain why some children with COVID-19 develop myocarditis (inflammation of the heart muscle), cardiogenic shock (inadequate blood flow due to heart failure) and cardiac arrest (sudden loss of heart function).

The aforementioned previous studies have described alterations in the number and morphology of peripheral blood cells in COVID-19 patients, including correlations between RBC indices and disease severity. However, characterizing RBC mechanical properties related to COVID-19 is crucial for understanding disease progression.

Real-time deformability cytometry (RT-DC) is a high-throughput technique that allows the characterization of peripheral blood cells by assessing their morphological and mechanical properties.

It has been successfully used to identify alterations in blood cell shape, membrane integrity, and deformation in other viral infections. Preliminary data from RT-DC analysis of peripheral blood cells in adult COVID-19 patients demonstrated increased heterogeneity in RBC size and deformation.

However, the specific cell-mechanical changes associated with SARS-CoV-2 infection in children remain unknown. Therefore, this study aimed to examine morphological and mechanical alterations of RBCs in SARS-CoV-2-seropositive children and adolescents compared to seronegative individuals, with a focus on the time since seroconversion.

Discussion

This new study revealed significant alterations in RBCs after SARS-CoV-2 infection in children and adolescents, with differences observed based on the time since seroconversion. Median RBC deformation was significantly higher in SARS-CoV-2-seropositive participants, even after adjusting for age and gender.

Increased RBC deformation may indicate fluidization of the cell membrane, possibly due to structural damage of membrane proteins and lipids observed in COVID-19 patients. The spike protein of SARS-CoV-2 was found to target the membrane-bound protein band-3, leading to membrane fragmentation and increased RBC deformation. Immune complex deposition and inflammation of the endothelium may further contribute to altered RBC membrane properties and increased deformability.

The study also found an increased standard deviation of brightness in RBCs after SARS-CoV-2 infection, reflecting structural changes within the cells. These changes may result from direct infection of RBCs or alterations in hemoglobin. Interestingly, participants who had received complete vaccination against SARS-CoV-2 also exhibited significantly increased RBC deformation compared to seronegative participants.

This finding suggests that altered RBC deformation may be a direct effect of SARS-CoV-2 spike protein presentation and part of the immune response against the virus. However, further validation is required due to the small number of vaccinated participants included in the study.

Subanalysis based on the time of seroconversion showed that increased median RBC deformation was only present until 6 months after SARS-CoV-2 infection, returning to levels observed in seronegative participants. This indicates a physiological recovery process following the acute infection, considering the average lifespan of RBCs.

Similar findings have been reported in recovered COVID-19 patients, where RBC deformation returned to normal after several months. These observations suggest that the compensatory capacity of children and adolescents plays a crucial role in preventing severe COVID-19 symptoms and pathologies.

Conclusion

In conclusion, SARS-CoV-2 infection in children and adolescents is associated with increased RBC deformation during the first 6 months after infection. This enhanced deformability may represent a compensatory mechanism during acute COVID-19, aiming to prevent severe pathological changes and symptoms.

Understanding the physiological processes involved in mild pediatric COVID-19 cases with successful recovery can provide insights into the pathomechanisms of severe COVID-19 and the onset of Long-COVID syndrome. The study also highlights the potential of RBC deformation as a read-out parameter for assessing these RBC changes, with implications for clinical diagnostics.

Further research, including prospective longitudinal case-control studies, is necessary to elucidate the time course of RBC alterations in Long COVID-19.

It is important to note that different techniques used to measure RBC deformation are not directly comparable, and results should be interpreted with reference to the specific method employed.


reference link: https://www.nature.com/articles/s41598-023-35692-6

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