Role of vitamin D in modulating the immune response to SARS-CoV-2 and other coronavirus infections.

In recent years, new data have been obtained on the significant prevalence of vitamin D (VD) deficiency in the population, and knowledge about the role of vitamin D in the regulation of many physiological processes in the body, including the functioning of the immune system, has increased. The SARS-CoV-2 pandemic has further highlighted the issue of an adequate immune response in vitamin D deficiency. Objective of the review. To present and summarize the evidence on the role of VD in different parts of the immune response in COVID-19, to analyze available studies of the VD status effect on the course and outcome of COVID-19 in patients from different population groups. Material and methods. A search of domestic and foreign literature on the role of VD in the immune response in respiratory viral infections and SARS-CoV-2, as well as practical measures of VD-status correction in COVID-19, was performed. We used Scopus, Web of Science, PubMed, Google Scholar, eLibrary, and Cyberleninka databases. Results. Numerous clinical and observational studies have found an association between 25-hydroxyvitamin D levels, COVID-19 severity, and mortality. This association can be explained by the multifaceted role of vitamin D in the physiology of the human immune and endocrine systems. On the immunological side, the active form of VD promotes the secretion of antimicrobial peptides responsible for inhibiting viral replication and stimulates autophagy by increasing the level of Beclin1 protein and decreasing the level of mTOR protein regulating cellular homeostasis. It leads to the presentation of antigens followed by activation of the antiviral pathway of type I interferons. VD also stabilizes intercellular junctions, including those in the airway epithelium, reducing their permeability to pathogens, stimulates the activity of angiotensin-converting enzyme-2, whose receptors are a conduit for SARS-CoV-2 into cells, and several pathophysiological responses associated with the disease symptoms and acute lung injury. Adequate vitamin D status can provide significant benefits during the pandemic. Conclusion. To date, ideas about the role of vitamin D in regulating the immune response in respiratory infections have significantly expanded. However, its use in the complex preventive measures and adjuvant therapy of viral infections, including COVID-19, should be the subject of further scientific research.Copyright © 2023, Media Sphera Publishing Group. All rights reserved.

Role of vitamin D in modulating the immune response to SARS-CoV-2 and other coronavirus infections

In recent years, new data have been obtained on the significant prevalence of vitamin D (VD) deficiency in the population, and knowledge about the role of vitamin D in the regulation of many physiological processes in the body, including the functioning of the immune system, has increased. The SARS-CoV-2 pandemic has further highlighted the issue of an adequate immune response in vitamin D deficiency. Objective of the review. To present and summarize the evidence on the role of VD in different parts of the immune response in COVID-19, to analyze available studies of the VD status effect on the course and outcome of COVID-19 in patients from different population groups. Material and methods. A search of domestic and foreign literature on the role of VD in the immune response in respiratory viral infections and SARS-CoV-2, as well as practical measures of VD-status correction in COVID-19, was performed. We used Scopus, Web of Science, PubMed, Google Scholar, eLibrary, and Cyberleninka databases. Results. Numerous clinical and observational studies have found an association between 25-hydroxyvitamin D levels, COVID-19 severity, and mortality. This association can be explained by the multifaceted role of vitamin D in the physiology of the human immune and endocrine systems. On the immunological side, the active form of VD promotes the secretion of antimicrobial peptides responsible for inhibiting viral replication and stimulates autophagy by increasing the level of Beclin1 protein and decreasing the level of mTOR protein regulating cellular homeostasis. It leads to the presentation of antigens followed by activation of the antiviral pathway of type I interferons. VD also stabilizes intercellular junctions, including those in the airway epithelium, reducing their permeability to pathogens, stimulates the activity of angiotensin-converting enzyme-2, whose receptors are a conduit for SARS-CoV-2 into cells, and several pathophysiological responses associated with the disease symptoms and acute lung injury. Adequate vitamin D status can provide significant benefits during the pandemic. Conclusion. To date, ideas about the role of vitamin D in regulating the immune response in respiratory infections have significantly expanded. However, its use in the complex preventive measures and adjuvant therapy of viral infections, including COVID-19, should be the subject of further scientific research.

Deregulation of the Expression of Beclin1 and Light Chain 3(LC3), Autophagy-Related Genes, in COVID-19 Patients.

Background: The autophagy machinery is reported to be employed by Coronaviruses during their replication. Beclin-1 (BECN1) and protein 1 light chain 3 (LC3) are two key elements in the autophagy process, and their inhibition can prevent the replication of some coronaviruses in vitro. Here, we aimed to investigate the expression levels of Beclin-1 and LC3 in COVID-19 patients and healthy controls, hoping to find new therapeutic targets. Methods: This cross-sectional study was conducted in Imam Reza and Ghaem University Hospitals, Mashhad, Iran. Nasopharyngeal samples of 68 consecutive Covid-19 patients and 61 healthy controls, who have been referred to the laboratories for COVID-19 PCR testing between 21 March to 21 September 2021, were used in order to evaluate the expression of BECN1 and LC3 genes using the Real-time quantitative PCR method. Demographic and other laboratory findings of patients were extracted from the hospital electronic system. SPSS Statistics 16.0 and Graph Pad Prism 8.4.2 soft wares were used for statistical analysis. Non-parametric tests were used. Results: BECN1 expression was significantly higher in COVID-19 patients compared to the controls (14.37±18.84 vs. 4.26±7.39, p=0.001). The expression of LC3 gene was significantly lower in patients compared to the controls (1.01±1.06 vs. 1.49±1.12, p=0.007). There was no significant correlation between the expression levels of BECN1 and LC3. Patients with lower BECN1 expression showed significantly higher RBC counts, higher Urea and lower HCO3 levels. The patients in LC3Low group showed significantly lower MCH, MCHC and PH levels compared to the others. Conclusion: Regarding the significant difference in the expression of BECN1 and LC3 in COVID-19 patients compared to the controls, these molecules may have a role in the pathogenesis of this disease. In case of further confirmation of this role, these molecules may be used as possible therapeutic targets.

Hydroxychloroquine (HCQ) Exhibits Better Binding to the Main Protease (Mpro) Compared to Spike Protein (S protein) of SARS-CoV-2: An In-silico Analysis

Background: Despite various efforts in preventing and treating SARS-CoV-2 infec-tions;transmission and mortality have been increasing at alarming rates globally. Since its first oc-currence in Wuhan, China, in December 2019, the number of cases and deaths due to SARS-CoV--2 infection continues to increase across 220 countries. Currently, there are about 228 million cases and 4.6 million deaths recorded globally. Although several vaccines/drugs have been reported to prevent or treat SARS-CoV-2, their efficacy to protect against emerging variants and duration of protection are not fully known. Hence, more emphasis is given to repurpose the existing pharmacological agents to manage the infected individuals. One such agent is hydroxychloroquine (HCQ), which is a more soluble derivative of antimalarial drug chloroquine. HCQ has been tested in clinical trials to mitigate SARS-CoV-2 infection-induced complications while reducing the time to clinical recovery (TTCR). However, several concerns and questions about the utility and efficacy of HCQ for treating SARS-CoV-2 infected individuals still persist. Identifying key proteins regulated by HCQ is likely to provide vital clues required to address these concerns. Objective: The objective of this study is to identify the ability of HCQ for binding to the most wide-ly studied molecular targets of SARS-CoV-2 viz., spike glycoprotein (S protein), and main pro-tease (Mpro, also referred as chymotrypsin like protease) using molecular docking approaches and correlate the results with reported mechanisms of actions of HCQ. Methods: X-ray crystallographic structures of spike glycoprotein and main protease of SARS-CoV-2 were retrieved from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB). The structure of Hydroxychloroquine was retrieved from the PubChem compound database. The binding interactions of the HCQ with target proteins were predicted using C-Docker algorithm, and visualized using Discovery studio visualizer. Results: Data from molecular docking studies showed very strong binding of HCQ to the main pro-tease compared to spike glycoprotein. Conclusion: The antiviral activity of HCQ is attributed to its ability to bind to the main protease compared to surface glycoprotein. Therefore, future studies should focus more on developing a combination agent/strategy for targeting surface glycoprotein and main protease together.

Cardiac Glycosides as Autophagy Modulators.

Drug repositioning is one of the leading strategies in modern therapeutic research. Instead of searching for completely novel substances and demanding studies of their biological effects, much attention has been paid to the evaluation of commonly used drugs, which could be utilized for more distinct indications than they have been approved for. Since treatment approaches for cancer, one of the most extensively studied diseases, have still been very limited, great effort has been made to find or repurpose novel anticancer therapeutics. One of these are cardiac glycosides, substances commonly used to treat congestive heart failure or various arrhythmias. Recently, the antitumor properties of cardiac glycosides have been discovered and, therefore, these compounds are being considered for anticancer therapy. Their mechanism of antitumor action seems to be rather complex and not fully uncovered yet, however, autophagy has been confirmed to play a key role in this process. In this review article, we report on the up-to-date knowledge of the anticancer activity of cardiac glycosides with special attention paid to autophagy induction, the molecular mechanisms of this process, and the potential employment of this phenomenon in clinical practice.

Contribution of autophagy machinery factors to HCV and SARS-CoV-2 replication organelle formation.

Positive-strand RNA viruses replicate in close association with rearranged intracellular membranes. For hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), these rearrangements comprise endoplasmic reticulum (ER)-derived double membrane vesicles (DMVs) serving as RNA replication sites. Cellular factors involved in DMV biogenesis are poorly defined. Here, we show that despite structural similarity of viral DMVs with autophagosomes, conventional macroautophagy is dispensable for HCV and SARS-CoV-2 replication. However, both viruses exploit factors involved in autophagosome formation, most notably class III phosphatidylinositol 3-kinase (PI3K). As revealed with a biosensor, PI3K is activated in cells infected with either virus to produce phosphatidylinositol 3-phosphate (PI3P) while kinase complex inhibition or depletion profoundly reduces replication and viral DMV formation. The PI3P-binding protein DFCP1, recruited to omegasomes in early steps of autophagosome formation, participates in replication and DMV formation of both viruses. These results indicate that phylogenetically unrelated HCV and SARS-CoV-2 exploit similar components of the autophagy machinery to create their replication organelles.

Beclin-1, an autophagy-related protein, is associated with the disease severity of COVID-19.

AIMS: Coronavirus disease 2019 (COVID-19), which is a highly contagious disease, is an ongoing outbreak worldwide with high morbidity and mortality. The approaches targeting the autophagy processes might have promising diagnostic and therapeutic values against Coronavirus infection. Here, we aimed to investigate the relationship of Beclin-1 (BECN1), an autophagy-related protein, with blood parameters and the clinical severity in patients with COVID-19. MATERIALS AND METHODS: We enrolled 108 patients with COVID-19 and 21 healthy controls in this study, from September 2020 to January 2021 and divided all patients into two groups according to the severity of the disease: The non-severe group and the severe group. BECN1 levels and blood parameters were measured with Enzyme-Linked Absorbent Assay and routine techniques, respectively. KEY FINDINGS: Serum BECN1 levels were increased in patients with COVID-19 compared to the healthy controls, and its concentrations were significantly higher in the severe group than in the non-severe group (p < 0.001). BECN1 levels showed a significantly positive correlation with coagulation markers such as D-dimer and Fibrinogen (FIB) and inflammation markers such as C-reactive protein (CRP), Procalcitonin (PCT), Ferritin and biochemical markers such as Blood urea nitrogen and Lactate dehydrogenase (p < 0.001). We detected that areas under the ROC curve for BECN1, D-dimer, FIB, PCT, CRP and Ferritin were 0.8662, 0.9110, 0.8278, 0.9996 and 0.9284, respectively (p < 0.0001). SIGNIFICANCE: BECN1 may serve as a predictive biomarker in evaluating the disease severity of COVID-19. Our data suggest that BECN1 mediated-autophagy modulation might have a promising value in improving the clinical outcomes of COVID-19.