Lipids, statins and susceptibility to SARS-CoV-2 and influenza A viruses

The respiratory viruses, influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have demonstrated their action to cause significant morbidity, mortality and socio-economic disruption. The 1918 influenza pandemic caused 20–100 million deaths, with one-third of the world’s population being infected¹, while the current COVID-19 pandemic has resulted in 146 million confirmed cases and over 3 million deaths to date². Our focus here is to review the potential for statins to affect patient outcomes for these viral infections.

Statins are among the most highly prescribed drugs used in the treatment of hypercholesterolemia, a major cause of cardiovascular disease. Diet has an effect on cholesterol levels, but our endogenous synthesis of cholesterol accounts for age-associated increases. To reduce plasma cholesterol to medically recommended levels of less than 4 mM, doctors prescribe statins to inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) (Figure 1). Cholesterol is essential so it is important that statins do not block cholesterol synthesis completely. As shown in Figure 1, inhibition of HMGCR also affects other L-mevalonate pathways including protein prenylation³. Interestingly, statins can target any HMGCR, including HMGCRs of pathogenic Candida species and Aspergillus fumigatus⁴.

Figure 1.  Molecular targets of statin treatment during SARS-CoV-2 infection showing inhibition of HMG-CoA reductase resulting in multiple effects.

Statins were discovered in the soil fungus Aspergillus terreus, which is currently used to produce lovastatin, a precursor of simvastatin. Simvastatin and atorvastatin were the first blockbuster drugs, but many additional statins have since been produced. Statins are used to inhibit HMGCR in the liver, reducing plasma cholesterol levels. Cholesterol is also an essential component of cell membranes, which become integrated into viral envelopes, leading us to review what is known about the effect of statins on SARS-CoV-2 and the other respiratory virus associated with pandemics, influenza A virus (IAV). Our findings are summarised in Table 1.

Table 1.  Effects of cholesterol and statins on SARS-CoV-2 and IAV infections.

Cholesterol is a vital part of IAV and SARS-CoV-2. During viral budding, lipids and cholesterol from infected host cells become part of the viral envelope¹⁹. Dietary cholesterol levels were shown to affect influenza infection in a mouse study⁷. Compared to a controlled diet group, mice with a 2% cholesterol diet experienced increased morbidity over a 5-week period.

The underlying low-grade chronic inflammation due to the release of the pro-inflammatory mediators from adipocytes of obese individuals exacerbates the cytokine storm observed in COVID-19 disease²⁰. Obesity is also associated with the upregulation of ACE2 expression. ACE2 is a receptor for SARS-CoV-2 spike proteins, so its upregulation could further enhance viral attachment and entry to the host tissue and increase severity²¹. The higher content of lipid rafts with high cholesterol levels in obese patients may also support SARS-CoV-2 attachment to host cells and its subsequent replication. Importantly, cholesterol-rich lipid rafts in the host cell membrane are favourable for enveloped viruses making cholesterol reduction a general strategy to thwart enveloped virus infection²².

Statins have been investigated to determine whether they affect outcomes of IAV and SARS-CoV-2 infections. While benefits of atorvastatin and rosuvastatin have been demonstrated in a model of IAV infection in cell culture^14,15, the benefits to statin users have varied. A study comparing 5181 statin users with 5181 non-users found small benefits that were not statistically significant¹⁶. On the other hand, in a large-scale matched cohort study (n = 76 232), moderate dose usage of statin was found beneficial by significantly reducing the risk of death due to COPD and influenza¹⁸. Similarly, in another multistate surveillance study, statin usage in patients hospitalised due to influenza was found associated with reduced mortality¹⁷. As influenza induces pro-inflammatory pathways by triggering the innate immune system, the anti-inflammatory pleotropic properties of statins have been studied to counteract it. Through in vitro tests, statins were able to inhibit IAV proliferation and possibly reduce inflammation by targeting Rho/Rho kinase pathways¹⁴. Several studies of patients with SARS-CoV-2 infection demonstrated the beneficial effects of statins, significantly reducing mortality rates and disease severity^9–12.

It is now clear that statins have several additional effects apart from cholesterol synthesis inhibition which deserves further investigation.

Statins show promise in reducing severity of IAV and SARS-CoV-2, which could be attributed to inhibition HMGCR and a number of other targets. Specifically, the inhibition of protein prenylation has multiple effects including enhancing cytokine-induced inflammation, regulating proteostasis, and post-translational modifications of the intracellular proteins. These events are most likely to be involved in SARS-CoV-2 pathogenesis and viral proliferation as the virus utilises host machinery for survival and proliferation. Knowledge of the targeting of statins may improve the development of therapies for COVID-19 and IAV.

Ian Macreadie is the Editor-in-Chief of Microbiology Australia, but was blinded from the peer-review process for this paper.

This study did not receive specific funding.