Cholesterol-modifying drugs in COVID-19.

Nathalie M Schmidt,Mala K Maini,Peter A C Wing,Jane A Mckeating

doi:10.1093/oxfimm/iqaa001

Nathalie M Schmidt, Mala K Maini + Show 2 more

Open Access

https://doi.org/10.1093/oxfimm/iqaa001

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Abstract

Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome. Here, we consider mechanisms by which dyslipidaemia and the use of cholesterol-modifying drugs could influence the virus–host relationship. Cholesterol is essential for the assembly, replication and infectivity of enveloped virus particles; we highlight several cholesterol-modifying drugs with the potential to alter the SARS-CoV-2 life cycle that could be tested in in vitro and in vivo models. Although cholesterol is an essential component of immune cell membranes, excess levels can dysregulate protective immunity and promote exaggerated pulmonary and systemic inflammatory responses. Statins block the production of multiple sterols, oxysterols and isoprenoids, resulting in a pleiotropic range of context-dependent effects on virus infectivity, immunity and inflammation. We highlight antiviral, immunomodulatory and anti-inflammatory effects of cholesterol-modifying drugs that merit further consideration in the management of SARS-CoV-2 infection.

Highlights

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the dynamic and variable nature of host–pathogen interactions, with the severity ranging from asymptomatic infection to fatal acute respiratory distress syndrome (ARDS)
Infection with severe acute respiratory syndrom coronavirus 2 (SARS-CoV-2) is more likely to lead to poor outcomes in the elderly and those with cardiovascular disease, obesity or metabolic syndrome
Several lines of evidence provide a rationale for high cholesterol predisposing to a worse outcome in SARS-CoV-2 infection, by dysregulating protective immunity and promoting exaggerated pulmonary and systemic inflammatory responses

Summary

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the dynamic and variable nature of host–pathogen interactions, with the severity ranging from asymptomatic infection to fatal acute respiratory distress syndrome (ARDS). Statins reduce intracellular and extracellular cholesterol by targeting 3-hydroxy-3-methylglutarylCoenzyme A (HMG-CoA) reductase, the rate-limiting first step in the cholesterol biosynthesis (mevalonate) pathway; they inhibit the synthesis of multiple other biologically active sterols, oxysterols and key isoprenoid intermediates [32, 33] Their inhibition of protein prenylation via the reduction of isoprenoid intermediates could provide an additional mechanism to inhibit SARS-CoV-2 infectivity (reviewed by Marakasova et al [34]). The many other ways in which statins can exert anti-inflammatory effects include their capacity to stabilize endothelial leakage, limit leukocyte transmigration and increase local nitric oxide [32] These are likely to be relevant to the pathology of SARS-CoV-2, which can include endothelial cell infection and endotheliitis in several organs [66]. Data from several large randomized trials testing the addition of statins for ARDS [70,71,72] (of nonSARS-CoV-2 aetiologies) showed no overall benefit or capacity to combat rising levels of IL-18 [73], suggesting they are unlikely to exert useful anti-inflammatory activity if started in the advanced stages of COVID-19

CONCLUSIONS

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