SARS-CoV-2, COVID-19 and the Ageing Immune System.

The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of ageing have highlighted how ageing pathways control not only lifespan but also healthspan, the healthy years of life. Here, we discuss the ageing immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target ageing-associated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in the elderly but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

Modeling Predictive Age-Dependent and Age-Independent Symptoms and Comorbidities of Patients Seeking Treatment for COVID-19: Model Development and Validation Study.

BACKGROUND: The COVID-19 pandemic continues to ravage and burden hospitals around the world. The epidemic started in Wuhan, China, and was subsequently recognized by the World Health Organization as an international public health emergency and declared a pandemic in March 2020. Since then, the disruptions caused by the COVID-19 pandemic have had an unparalleled effect on all aspects of life. OBJECTIVE: With increasing total hospitalization and intensive care unit admissions, a better understanding of features related to patients with COVID-19 could help health care workers stratify patients based on the risk of developing a more severe case of COVID-19. Using predictive models, we strive to select the features that are most associated with more severe cases of COVID-19. METHODS: Over 3 million participants reported their potential symptoms of COVID-19, along with their comorbidities and demographic information, on a smartphone-based app. Using data from the >10,000 individuals who indicated that they had tested positive for COVID-19 in the United Kingdom, we leveraged the Elastic Net regularized binary classifier to derive the predictors that are most correlated with users having a severe enough case of COVID-19 to seek treatment in a hospital setting. We then analyzed such features in relation to age and other demographics and their longitudinal trend. RESULTS: The most predictive features found include fever, use of immunosuppressant medication, use of a mobility aid, shortness of breath, and severe fatigue. Such features are age-related, and some are disproportionally high in minority populations. CONCLUSIONS: Predictors selected from the predictive models can be used to stratify patients into groups based on how much medical attention they are expected to require. This could help health care workers devote valuable resources to prevent the escalation of the disease in vulnerable populations.

Pathophysiology of Cardiovascular Complications in COVID-19.

Numerous recent studies have shown that patients with underlying cardiovascular disease (CVD) are at increased risk of more severe clinical course as well as mortality of COVID-19. Also, the available data suggests that COVID-19 is related to numerous de novo cardiovascular complications especially in the older population and those with pre-existing chronic cardiometabolic conditions. SARS-CoV-2 virus can cause acute cardiovascular injury, as well as increase the risk of chronic cardiovascular damage. As CVD seem to be the major comorbidity in critically unwell patients with COVID-19 and patients often die of cardiovascular complications, we review the literature and discuss the possible pathophysiology and molecular pathways driving these disease processes: cytokine release syndrome, RAAS system dysregulation, plaque destabilization and coagulation disorders with the aim to identify novel treatment targets. In addition, we review the pediatric population, the major cause of the cardiovascular complications is pediatric inflammatory multisystem syndrome that is believed to be associated with COVID-19 infection. Due to the increasingly recognized CVD damage in COVID-19, there is a need to establish clear clinical and follow-up protocols and to identify and treat possible comorbidities that may be risk factors for the development of cardiovascular complications.

Cholesterol in Relation to COVID-19: Should We Care about It?

Current data suggest that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease-19 (COVID-19) seems to follow a more severe clinical course in patients with cardiovascular disease (CVD), hypertension, and overweight/obesity. It appears that lipid-lowering pharmacological interventions, in particular statins, might reduce the risk of cardiovascular complications caused by COVID-19 and might potentially have an additional antiviral activity. It has been shown that high cholesterol levels are associated with more lipid rafts, subdomains of the plasma membrane that can harbour angiotensin-converting enzyme 2 (ACE2) receptors for the S-protein of SARS-CoV-2. Evidence of the importance of cholesterol for viral entry into host cells could suggest a role for cholesterol-lowering therapies in reducing viral infectivity. In addition to their lipid-lowering and plaque-stabilisation effects, statins possess pleiotropic effects including anti-inflammatory, immunomodulatory, and antithrombotic activities. Lower rates of mortality and intubation have been reported in studies investigating statin therapy in influenza infection, and statin therapy was shown to increase viral clearance from the blood during chronic hepatitis C infection. Statins may also serve as potential SARS-CoV-2 main protease inhibitors, thereby contributing to the control of viral infection. In this review, we elaborate on the role of cholesterol level in the process of the coronavirus infection and provide a critical appraisal on the potential of statins in reducing the severity, duration, and complications of COVID-19.

Statins and the COVID-19 main protease: in silico evidence on direct interaction.

INTRODUCTION: No proven drug and no immunisation are yet available for COVID-19 disease. The SARS-CoV-2 main protease (Mpro), a key coronavirus enzyme, which is a potential drug target, has been successfully crystallised. There is evidence suggesting that statins exert anti-viral activity and may block the infectivity of enveloped viruses. The aim of this study was to assess whether statins are potential COVID-19 Mpro inhibitors, using a molecular docking study. MATERIAL AND METHODS: Molecular docking was performed using AutoDock/Vina, a computational docking program. SARS-CoV-2 Mpro was docked with all statins, while antiviral and antiretroviral drugs - favipiravir, nelfinavir, and lopinavir - were used as standards for comparison. RESULTS: The binding energies obtained from the docking of 6LU7 with native ligand favipiravir, nelfinavir, lopinavir, simvastatin, rosuvastatin, pravastatin, pitavastatin, lovastatin, fluvastatin, and atorvastatin were -6.8, -5.8, -7.9, -7.9, -7.0, -7.7, -6.6, -8.2, -7.4, -7.7, and -6.8 kcal/mol, respectively. The number of hydrogen bonds between statins and amino acid residues of Mpro were 7, 4, and 3 for rosuvastatin, pravastatin, and atorvastatin, respectively, while other statins had two hydrogen bonds. CONCLUSIONS: These results indicate, based upon the binding energy of pitavastatin, rosuvastatin, lovastatin, and fluvastatin, that statins could be efficient SARS-CoV-2 Mpro inhibitors. This is supported by the fact that the effects of some statins, especially pitavastatin, have a binding energy that is even greater than that of protease or polymerase inhibitors. However, further research is necessary to investigate their potential use as drugs for COVID-19.