Are statins beneficial for the treatment of SARS-CoV-2 infection?

Introduction

Since December 2019, a novel coronavirus disease (COVID-19) caused by SARS-CoV-2 rapidly spread across the world. As the number of infected patients increases continuously, scientists, physicians and other medical experts have been racing to get a better understanding of the virus’s genetic makeup and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To date, there are no specific antiviral drugs or vaccine against SARS-CoV-2 infection for potential therapy of humans. The only option available is using broad-spectrum antiviral drugs that could attenuate virus infection until the specific antiviral becomes available. It is clear, however, that more research is urgently needed to find broad-spectrum agents that provide an opportunity to treat COVID-19. Most scientists around the globe are racing to develop a new drug or vaccine that targets virus-specific components, and few accept the idea of treating and enhances the host response with generic drugs. Although many different treatment options have been proposed through various approaches, no specific treatment is currently available for COVID-19 to date. One of the main reasons for this is most of the identified drugs that may work to combat the coronavirus were not rigorously evaluated for in vitro and in vivo studies. However, a bottom-up approach to treatment that targets the host response to these viruses by using widely available and inexpensive generic drugs could be an effective way to reduce the morbidity and mortality from COVID-19.

Coronaviruses and lipids

Coronaviruses are enveloped viruses. The envelopes are typically derived from portions of the host cell membranes, composed mainly of lipid and protein. As such, the protein and lipid compositions of both the viral envelope and the host cell membrane play crucial roles in virus infection. Understanding the interactions between viruses and their host cells will provide fundamental insights into the molecular mechanisms of viral pathogenesis and on host cell biology.

Enveloped viruses acquire their lipid envelopes to achieve various physiological processes, including viral entry, genomic replication, and the assembly and budding of virions, thereby resulting in pathological damage to the host cellular membranes (Millet and Whittaker, 2018). These constructions also determine the stability characteristics of the virus particle, such as resistance to chemical or physical inactivation. Therefore, interrupting any stages of the viral life cycle would become a potential therapeutic target for developing antiviral therapies.

In the case of SARS-CoV, fusion takes place at the host cell membrane and viral envelope, which are heavily dependent on the presence of lipid microdomains, or ‘rafts’, that are enriched in cholesterol, sphingolipids, glycosyl-phosphatidylinositol (GPI)-anchored proteins, and a specific set of associated proteins often cell receptors (Lu et al., 2008). Lipid rafts are major structural components in plasma membranes that play a crucial role in immunity, including phagocytosis and recognition of infected cells by acting as signalling platforms on the cell membrane, so disruption of rafts during entry or assembly often ‘hides’ the virus from immune response (Sviridov and Bukrinsky, 2014). On the other hand, disruption of lipid rafts by cholesterol depletion has been shown to enhance the release of viral particles from infected cells and a decrease in the infectivity of virus particles (Barman and Nayak, 2007).

Cholesterol is a critical structural component of lipid rafts; some reports suggest that lipid rafts promote fusion of the viral and target cell membranes, as depletion of cholesterol from the viral or host cell membranes might lead to inhibits virus-cell fusion (Barman and Nayak, 2007). Furthermore, the fusion of several viruses has been shown to be dependent on the presence of cholesterol in the target cell membranes (Graham et al., 2003; Huang et al., 2006; Sun and Whittaker, 2003). Moreover, lipid rafts have been suggested to serve as contact zones between virus and target cell and facilitate cell-to-cell transmission of infection, known as the virological synapse (Ono, 2010).

To survive, host cells must be able to repair and replace their lipid bilayers efficiently. Viral membranes, although derived from the host cells, lack these metabolic and repair pathways, leaving their membranes susceptible to specific disruption (Wolf et al., 2010). Thus, the host-derived viral membrane represents a susceptible target for antiviral inhibitors. Studies showed that depletion of cellular membrane cholesterol significantly reduced plaque development 2- to 20-fold, depending on the infecting coronavirus strain, while supplementations increased susceptibility 2- to 10-fold (Thorp and Gallagher, 2004). The coronavirus-cell membrane fusion process was specifically inhibited or augmented by cholesterol depletion or supplementation (Thorp and Gallagher, 2004).

SARS-CoV-2 and host innate immune responses

The outcome of SARS-CoV-2 infection is largely determined by virus-host interaction. Understanding the interplay between virus and host antiviral defence will shed new light on viral pathogenesis and the development of a novel therapeutic strategy in treating SARS-CoV-2 infected patients. The complex interaction between SARS-CoV-2 and the host begins immediately on viral contact with host target cells. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of mortality among patients with COVID-19. Evidence suggests that hyperinduction of proinflammatory cytokines, which is also known as cytokine release syndrome (CRS), contributes to life-threatening manifestations of multiple organ dysfunction in coronavirus disease 2019 (Liu et al., 2020).

Higher plasma levels of inflammatory cytokines and chemokines including interleukin (IL)-1b, IL-2, IL-6, IL-7, IL-10, granulocyte-colony stimulating factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte chemoattractant protein (MCP1), macrophage inflammatory protein 1 alpha (MIP1A) and tumour necrosis factor (TNF)-α were found in COVID-19, which implied a cytokine release syndrome occurred (Cao, 2020; Huang et al., 2020; Xu et al., 2020). Moreover, severe lymphopenia with hyperactivated proinflammatory T cells and decreased regulatory T cells is commonly seen in patients with COVID-19 (Huang et al., 2020). In addition, the post-mortem histopathology from a patient who died from severe infection with COVID-19 revealed tissue necrosis and interstitial macrophage and monocyte infiltrations in the lung, heart and gastrointestinal mucosa (Xu et al., 2020; Yao et al., 2020). Therefore, attenuating the detrimental host immune response by immunomodulators and anti-inflammatory agents such as statins may be a beneficial addition to anti-coronavirus therapy.

Antiviral effects of statins

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors widely used for the treatment of hypercholesterolemia (Moghadasian, 1999). Beside their cholesterol-lowering effect, statins have been reported to have antiviral activity against a variety of viruses, including HIV (del Real et al, 2004), Hepatitis C virus (Andrus and East, 2010), dengue virus (Martínez-Gutierrez et al., 2011), influenza virus (Mehrbod et al., 2014), Ebola virus (Shrivastava-Ranjan et al., 2018) and Zika virus (Españo et al., 2019) by inhibiting the cholesterol/isoprenoid pathway. Enveloped viruses like SARS-CoV-2 are highly dependent on their lipid envelopes for entry and replications into host cells (Sun and Whittaker, 2003). Previous studies demonstrate that cholesterol depletion from the plasma membrane of the target cells reduces the efficiency of infection by coronaviruses (Glende et al., 2008). Recently, it was revealed that linoleic acid (LA) and arachidonic acid (AA) are able to inhibit the replication level of coronavirus in cell culture, suggesting that the LA–AA metabolism axis is a common and essential pathway that could modulate coronavirus replication (Yan et al., 2019). Notably, statins have been reported to increase the plasma concentration of AA and LA (Levine, 2003). Despite the possible antiviral effect of statins, as monotherapy it could be insufficient for the treatment of coronavirus infections. However, several studies have demonstrated that the addition of statins to antiviral therapy increases sustained viral response, rapid virologic response and early virologic response rates without the occurrence of additional adverse events (Verpaalen et al., 2014). On the other hand, there is a close correlation between cholesterol levels and type 1 IFN response. High levels of cholesterol induce a poor IFN response (Liu et al., 2013). Thus, the reduction in levels of cholesterol might contribute to an increase in IFN response to SARS-CoV-2. To date, no reports have been published describing the direct effects of statins on the molecular and clinical pathophysiological profiles of experimental or clinical SARS-CoV-2 infections. Nonetheless, the evidence outlined above suggest the possibility that treatment and prophylaxis with statins might alter the clinical course and outcome of SARS-CoV-2 pandemic.

Anti-inflammatory and immunomodulatory effects of statins

In addition to their direct effect on virus entry and replications into host cells, statins are known for their anti-inflammatory and immunomodulatory effects. Indeed, it has been demonstrated that statins inhibit the secretion of proinflammatory cytokines IL-1, IL-6, TNF-α, IFN-γ, inhibit MCP-1 expression and reduction in the levels of plasma C-reactive protein (Blanco-Colio et al., 2003). It has also been noted that statins suppress T-cell activation (Overton et al., 2014; Ulivieri et al., 2008). Furthermore, statins have been shown to have TLR-MYD88 antagonist effects and attenuate activation of the NF-κB, which is a hallmark of coronavirus infections (Yuan, 2015). Accordingly, many observational and experimental studies suggested that statin treatment may be associated with a better prognosis in severe infections, suggesting that statins may act acutely to prevent organ dysfunction (Calisto et al., 2010; Gui et al., 2017; Novack et al., 2009).

Conclusion

Cholesterol metabolism is an attractive target for antiviral therapy as it may serve two purposes at once: suppress viral replication and correct changes in cholesterol metabolism caused by the infection. Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics and preventive agents. Importantly, understanding this basic information about coronavirus lipid targets will not only aid the public health against SARS-CoV-2 but also help in advance to target new coronaviruses that may emerge in the future. From this perspective, these generic drugs (statins) proposed in this review might be effective against SARS-CoV-2 infections either as single agents or in combination with other antiviral agents. They have the potential to be used as prophylaxis or therapy against SARS-CoV-2. Certainly, they will contribute to the protection against inflammation possibly associated with SARS-CoV-2, by regulating cytokine overexpression and modulating the intense inflammatory response. Nevertheless, more comprehensive research on the interactions between statins and SARS-CoV-2 and host immune responses needs to be carried out. This may lead to the development of more potent statins based on better profiles of bioavailability, which will help open new promising therapeutic option for the treatment of COVID-19. Lastly, comprehensive clinical studies should verify the benefits of statins for the treatment of SARS-CoV-2 infection with some considerations: first, identify the patients who are most likely to respond to the desired effect of statins; second, identify the most effective dose and duration of statins use; and third, identify the biomarkers accurately reflecting the pleiotropic effects that are clearly indicative of a patient’s response to the statin. Furthermore, the administrative database should be used to search for reduced rates of hospitalisation and death due to COVID-19 among people taking statins. Positive results from such studies would provide physicians in all countries with something to offer patients for the treatment and prophylaxis of the COVID-19 pandemic. Generic statins will be widely distributed and inexpensive.