Abstract
Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses that can infect animal and human hosts. The infection induces mild or sometimes severe acute respiratory diseases. Nowadays, the appearance of a new, highly pathogenic and lethal coronavirus variant, SARS-CoV-2, responsible for a pandemic (COVID-19), represents a global problem for human health. Unfortunately, only limited approaches are available to treat coronavirus infections and a vaccine against this new coronavirus variant is not yet available. The plasma membrane microdomain lipid rafts have been found by researchers to be involved in the replication cycle of numerous viruses, including coronaviruses. Indeed, some pathogen recognition receptors for coronaviruses as for other viruses cluster into lipid rafts, and it is therefore conceivable that the first contact between virus and host cells occurs into these specialized regions, representing a port of cell entry for viruses. Recent data highlighted the peculiar pro-viral or anti-viral role played by autophagy in the host immune responses to viral infections. Coronaviruses, like other viruses, were reported to be able to exploit the autophagic machinery to increase their replication or to inhibit the degradation of viral products. Agents known to disrupt lipid rafts, such as metil-β-cyclodextrins or statins, as well as autophagy inhibitor agents, were shown to have an anti-viral role. In this review, we briefly describe the involvement of lipid rafts and autophagy in coronavirus infection and replication. We also hint how lipid rafts and autophagy may represent a potential therapeutic target to be investigated for the treatment of coronavirus infections.
Introduction
Coronaviruses (CoVs) are a large group of enveloped animal and human viruses, with a single-stranded positive-sense RNA genome. The Coronaviridae family, to which they belong, includes four genera of CoVs, indicated as Alphacoronavirus (αCoV), Betacoronavirus (βCoV), Gammacoronavirus (γCoV), and Deltacoronavirus (δCoV) (; ). αCoV and βCoV have evolutionary evolved from bats and rodents, and have been responsible for human infections; whereas δCoV and γCoV derive from avian species (Woo et al., 2012). αCoV and βCoV are further divided into subgroups, 1a-1b and 2a-2d, respectively, (; ; ; ) (Supplementary Figure S1). Coronaviruses have been regarded as etiologic agents of both relatively mild and severe respiratory infections/diseases in humans (Zhao et al., 2012; ). HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1 cause the common cold and mild upper respiratory diseases in immunocompetent hosts, although some of them can be potentially virulent in infants, young children, and elder individuals. Highly pathogenic human coronaviruses, responsible for more severe respiratory diseases, include SARS-CoV that caused the 2003 pandemic outbreak of severe respiratory tract infection (), MERS-CoV, responsible for the 2012 outbreak in Middle Eastern countries (Zaki et al., 2012), and the novel SARS-CoV-2, actually causing a pandemic of severe pneumonia that started in China in December 2019 (; Zhu et al., 2020).
Coronavirus and coronavirus-like infections have been described also in domestic and wild animals, such as swine [porcine transmissible gastroenteritis virus and porcine epidemic diarrhea virus], cattle (BCoV), horses, camels, cats, dogs, rodents, birds, bats, rabbits, ferrets, mink, and various wildlife species (; ; ; ; Ye et al., 2020). Although many coronavirus infections are subclinical in animals, however, they cause a range of diseases that can have serious consequences for animal health as well as for the economic losses in livestock. In addition, domestic animals may have been important intermediate hosts for virus transmission from natural hosts to humans (; Ye et al., 2020).
Since only limited approaches are available to treat or prevent coronavirus infections (Zhang et al., 2020), the importance of identifying novel therapeutic targets is evident.
Viruses have evolved a close interplay with the host cell and the first encounter between the virus and target cell occurs at the plasma membrane. Lipid rafts are specialized plasma membrane microdomains involved in important processes of the virus infections and of the host target cells ().
Viruses exploit lipid rafts to gain infection of the target cells; therefore, pharmacologic depletion or disruption of lipid rafts may provide a tool to reduce or inhibit viral replication ().
Furthermore, it has been widely demonstrated that lipid rafts play a fundamental role in autophagic machinery: they are associated with autophagosome morphogenesis, either in the initiation or in the maturation phases ().
Autophagy, a cell process involved in cellular homeostasis, stress, and immune responses to viral infections, is a two-edged process in virus infections, since it may have pro- or anti-viral roles (; ). Viruses, on the other side, during co-evolution with the host cell, developed mechanisms to usurp/exploit the host autophagic system ().
This minireview reports on the available knowledge about the interplay between coronaviruses, including the SARS-CoV-2, with lipid rafts and autophagic pathways, in order to focus the attention to novel potential targets to inhibit coronavirus infections.
Lipid Rafts and Autophagy: Focus on Coronavirus
Lipid rafts are plasma membrane microdomains (10–200 nm) enriched in cholesterol, glycosphingolipids, and phospholipids. They are also found in the endoplasmic reticulum (ER) (), in the Golgi complex (), and on the membrane of endosomes (Sobo et al., 2007) and phagosomes (). There are two main types of lipid rafts based on their protein composition: “planar lipid rafts” and “caveolae” enriched by the proteins flotillin and caveolin, respectively (). Both possess a similar lipid composition that confers resistance to solubilization by non-ionic detergents at low temperatures (), and the characteristic of being able to be isolated in sucrose gradient (Sargiacomo et al., 1993). Because of their dynamic and heterogeneous structure, they can rapidly assemble and disassemble, changing their composition in response to intra- and extracellular stimuli (Simons and Toomre, 2000). A key component of lipid rafts is cholesterol that is the glue that maintains raft architecture, as demonstrated by the disorganization and disruption of lipid rafts upon depletion of plasma membrane cholesterol by the cholesterol depleting agent methyl-β-cyclodextrin (MβCD) (Simons and Ehehalt, 2002; Zidovetzki and Levitan, 2007). These membrane regions play an important role in a variety of cellular functions, but principally they recruit and concentrate several signaling molecules (Song et al., 1997; ; ; ) that, by interacting with caveolin and flotillin, form a sort of signal transduction platform. Therefore, lipid rafts are involved in many biological functions including endocytosis, signal transduction, cell communication, and regulation of autophagy (; Shi et al., 2015).
Because of their capacity to cluster into a “phagocytic synapse” several pathogen recognition receptors (Toll-like receptors, C-type lectin receptors), lipid rafts are the focus of intense research in the field of infection. In particular, they are involved in several steps along a viral infection, such as virus entry into the host cell (fusion and internalization), viral protein transport, viral assembly, and budding processes (). Several enveloped (HIV-1, influenza viruses, coronavirus, flavivirus) and non-enveloped (SV40 and Rrotavirus) viruses exploit the raft platform to bind to their specific receptors (; ; ; Takahashi and Suzuki, 2011).
Recent studies have implicated lipid rafts in coronavirus entry and egress through a multistep endocytic process, although the detailed mechanism remains to be disclosed (). Figure 1 depicts a schematic view of the role of lipid rafts in two paradigmatic human coronaviruses, HCoV-229E and SARS-CoV, infections. Briefly, the receptors for the two coronaviruses, aminopeptidase N (APN/CD13) and angiotensin converting enzyme 2 (ACE2), respectively, are located into lipid rafts and play a fundamental role in the initial step of the virus infection. APN/CD13, a zinc-binding aminopeptidase, is expressed in several cell types (endothelial, granulocytic, and monocytic cells; epithelial cells of the kidney; respiratory tract and intestine) and is required also for porcine, canine, and feline coronavirus recognition. ACE2, encoded on the X chromosome, is a metalloprotease long known to be a key player in the renin–angiotensin system that co-localizes with caveolin-1 and GM1 and is expressed on type I and II pneumocytes, enterocytes, endothelial cells of the heart and kidney, epithelial cells of the kidney, and the testis (). SARS-CoV-2, the etiological agent of the COVID-19 pandemic, also binds ACE2 to infect host cells, by similarity to SARS-CoV, from which it differentiates for point mutations on the spike protein, essential for receptor binding (Wang et al., 2020; Yan et al., 2020). By analogy to SARS-CoV, it can be hypothesized that SARS-CoV-2 may also use lipid rafts for its entry into the host cells.
FIGURE 1
The steps following coronavirus entry are not clearly identified. A recent study demonstrated that SARS-CoV exploits the activity of cathepsin L, an endosomal cysteine protease, to initiate proteolysis and activation of membrane fusion within endosomes (Simmons et al., 2013). In addition, coronavirus mouse hepatitis virus (MHV) infection is inhibited when early endosome-associated proteins, RAB5 and EEA1, are down-regulated by siRNA () and infectious bronchitis virus (IBV) release of the nucleocapsid into the cytoplasm (Wang et al., 2018) occurs through the fusion with endosome–lysosome membranes. These data suggest that coronaviruses exploit the early and late endosome compartment after viral entry, as several other viruses (adenovirus, human papillomavirus, polyomavirus, African swine fever virus, and influenza virus) (; ; Spriggs et al., 2019).
Recent evidence shows that there is a close interplay between lipid rafts and autophagy during physiological cell function, as lipid rafts can regulate autophagy by interacting with autophagosomes and autophagy-related proteins, such as ATG5 and ATG12 (; ). In addition a functional and structural link between lipid rafts and autophagy comes from the evidence that chemical (e.g., MβCD, fumonisin B1) or biological (e.g., siRNA inhibition of key enzymes involved in the sphingolipids metabolism) molecules capable of altering the chemical composition or molecular organization of lipid rafts have also a strong impact on autophagy ().
Autophagy is an evolutionarily conserved (from yeast to mammals), selective, and finely regulated process that generates ATP and precursors for the synthesis of macromolecules () and is considered as a survival process put in place by cells under stressful conditions, such as pathogen microbial infections. It plays a key role in cellular homeostasis and is responsible for the turnover of cellular organelles (Yu et al., 2018), as its main function is to remove and recycle non-essential, damaged, or obsolete cellular components, such as whole organelles or macromolecules (). During autophagy, cytoplasmic portions are enclosed into double membrane bound vesicles (autophagosomes) that then fuse with late endosomes/lysosomes, whose contents are degraded by lysosomal proteases. Autophagy has been shown to have additional function in innate immunity, by degradation of viruses, or intracellular pathogens, as well as by presenting pathogen components to the immune system ().
Autophagy can have a pro-viral role, promoting virus infection and propagation, as well as an antiviral role, essentially depending on the virus strain, on the phase of infection, on the infected cell type, but also on the cellular microenvironment (). During co-evolution with their natural hosts, viruses developed the ability to hijack autophagic mechanisms to their advantage by using them for immune escaping, or using autophagosomes as a replicative niche. However, data on autophagy interplay with coronaviruses are scant so far, related on no more than 50 works published between 2004 and 2015. In general, it is suggested that CoVs can interact with some components of the autophagic pathway in an opposite way with a dual effect: utilizing autophagy components to promote viral replication and/or to inhibit degradation of viral products through the autophagic pathway (). In some coronaviruses, infection results are still contradictory, as in the case of MERS-CoV (), which has been reported to induce phosphorylation changes in key kinases, such as AKT1 and mTOR, that regulate the early steps of autophagic process (), thus stimulating autophagy in infected cells. In contrast, Gassen et al. reported that MERS-CoV activates the SKP2 kinase, consequently reducing Beclin1 (BECN1) activity and inhibiting the fusion of autophagosomes with lysosomes, which results in autophagy inhibition ().
In general, it has been hypothesized that coronaviruses would induce accumulation of autophagic vacuoles to obtain a larger availability of the membrane structure necessary for their replication (), which is consistent to the observed co-localization of the rodent coronavirus, MHV, replication complex, with the autophagic proteins LC3 and Apg12 (). Likewise, the SARS-CoV takes advantage of autophagic pathway to replicate and transcribe its own genome, as suggested by inhibition of its replication through inactivation of GSK-3 (glycogen synthase kinase-3), a serine/threonine kinase that inhibits autophagy, through the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) (Wu et al., 2009; Zúñiga et al., 2010). A very recent study showed that SARS-CoV-2, similar to MERS-CoV, strongly reduced the autophagic flux in infected cell lines downregulating the AMPK/mTORC1 pathway, altered autophagy-relevant signaling, and also reduced autophagosome/lysosome fusion efficiency (). As a result, the SARS-CoV-2 virus could take advantage of the autophagy reduction, thus preventing viral product degradation and enhancing double membrane vesicles (DMV) availability, indispensable for their replication.
The cell organelle most involved in the dynamic membrane changes is the ER. It is therefore not surprising that some coronaviruses, through the insertion of their trans-membrane glycoproteins at the ER level, are able to induce ER stress. This is the case, for example, of the ORF3 protein produced by porcine epidemic diarrhea virus (PEDV), which induced ER stress-dependent autophagy in different porcine and human cell types (Zou et al., 2019). In the same vein, MHV was observed to use the host machinery to export vesicular ER to originate membranes for the genesis of DMV. As regards the non-structural protein (NSP) 6 of the avian infectious bronchitis virus (IBV), a gamma-coronavirus, in addition to providing membranes useful for the replication of the virus, it could prevent its degradation within the lysosomes, effectively escaping the autophagy-based cellular defensive mechanisms. Similar properties have also been observed for MHV and SARS NSP6 proteins and PRRSV arterivirus NSP5, NSP6, and NSP7 ().
Discussion
Coronaviruses may represent a threat for human and animal health for their potential to cross the species barrier, thus acquiring human virulence, as evidenced by the previous SARS-CoV and MERS-CoV outbreaks and by the ongoing COVID-19 pandemic. Notwithstanding, treatment and prophylaxis measures to control coronavirus infections are lacking so far, either in humans or in livestock animals.
As outlined in this review, lipid rafts and autophagic pathways play a pivotal role in coronavirus infection, being critical for viral entry and replication, as well as for viral release from the host cells. Actually, lipid rafts are the focus of intense research in the field of infection, and it is conceivable to consider targeting some lipid raft components in order to inhibit virus infection at the cell level.
In particular, lipid raft disruption by cholesterol-depleting agents has been shown to inhibit infection of several microbes by blocking their entry into the host cells (; Thorp and Gallagher, 2004; ; ; ; ; ; ; Szczepanski et al., 2018; ; ; ; ; Table 1). In human immunodeficiency virus (), herpes simplex virus, and rotavirus infections, MβCD, a widely used raft-disrupting agent, has been shown to affect virus entry, thereby reducing their infectivity (; Wudiri et al., 2017). In addition, in Japanese encephalitis virus and dengue virus infection, disruption of lipid rafts by MβCD has been shown to decrease viral infection acting at both viral entry and intracellular replication step (). β-cyclodextrins are extensively utilized in pharmaceutical formulations as excipients to enhance solubility, bioavailability, and stability of many drugs (). In the light of the above-described antiviral activity, further studies on pharmacokinetic and safety of MβCD could foster its clinical application as an antimicrobial agent in humans. Statins, used in human therapy for their ability to inhibit cellular synthesis of cholesterol, have also been reported to have an anti-viral effect, inhibiting infection of flavivirus, such as dengue virus (DENV), hepatitis C virus (HCV), West Nile virus (WNV), and Zika virus (; ; ; ), and their application to inhibition of the coronavirus infection would be worth considering.
TABLE 1
| Drugs | Mechanism of action | Target virus | Antiviral effects | References |
| MβCD, Nystatin | Disrupt lipid raft architecture by depleting cell membrane cholesterol | CRCoV HCoV-229E HCoV-NL63 HCoV-OC43 IBV MERS-CoV MHV SARS-CoV-2 | Inhibit viral entry/endocytosis | ; Thorp and Gallagher, 2004; ; ; ; ; ; Szczepanski et al., 2018; ; |
| Statins (mevastatin) | Inhibit lipid raft formation by lowering cholesterol biosynthesis | IBV SARS-CoV-2 | Inhibit viral entry/endocytosis | ; ; |
| Chloroquine and Hydroxychloroquine | Interfere with lysosome-mediated autophagy function by increasing the endosomal/lysosomal pH | MERS-CoV HCoV-229E HCoV-OC43 SARS-CoV SARS-CoV-2 | Prevent viral fusion and inhibit the viral entry by endocytosis, uncoating and exit (exocytosis) process | ,,,,,,,,, |
| Rapamycin (Sirolimus) | Inhibits mammalian target of rapamycin (mTOR) kinase | MERS-CoV PEDV SARS-CoV-2 | Downregulates virus infection | |
| Nitazoxanide | Inhibits Akt/mTOR/ULK1 signaling pathway | HCoVOC43 MERS-CoV SARS-CoV-2 | Inhibits virus replication | Shakya et al., 2018; Yang et al., 2020 |
| Niclosamide | mTORC1 inhibitor | MERS-CoV SARS-CoV | Inhibits viral antigen synthesis | ; Xu et al., 2020 |
Function of lipid rafts and autophagy in coronavirus lifecycles: overview on drugs.
Likewise, the pharmacological modulation of autophagic processes can represent an attractive therapeutic strategy for elimination of the viral pathogen or containment of the infection (; ).
In fact, different drugs described as inhibitors or inducers of the autophagy that control host cell pathways process involved in coronavirus infection, have sparked interest for their potential antiviral activity (Shakya et al., 2018; ; Xu et al., 2020; Yang et al., 2020; Table 1). One of this, chloroquine (CQ), and its derivative hydroxychloroquine (HCQ), known as anti-malarial drugs (), which are able to inhibit autophagy by raising the lysosomal pH (), have also been evaluated for HIV infection (). Very recently, clinicians have paid attention to CQ and HCQ as a possible treatment of patients infected by the novel emerged SARS-CoV-2 (,,,,,,,,,). This insight is also supported by some recent works, including a recent publication by Gao et al. that indicates some positive effects of CQ on the course of pneumonia associated with the infection and on the reduction in healing (; ; ; Yu et al., 2020).
On the contrary, other studies have highlighted the ineffectiveness of these drugs both in the viremic phase and in respiratory complications (; ; ). Although some data, both referring to COVID-19 and SARS, have highlighted some positive effects of CQ and HCQ in the evolution of the disease, thus showing their therapeutic potential, at the moment, there are no data that can support the use of these drugs to control the entire pathological process related to SARS-CoV-2 ().
In the same vein, rapamycin, also known as sirolimus, an autophagy inducer already used as an immunosuppressant, has been tested, with some success, in the treatment of COVID-19 (NCT04341675) (). These cases may represent a repositioning of the drugs with clinical success in treatment areas beyond their original approved use. According to this, the antiviral in vitro activity of spermidine, niclosamide, and nitazoxanide (known autophagy inducers) vs. SARS-CoV-2 was recently reported (Shakya et al., 2018; ; Xu et al., 2020; Yang et al., 2020). Thus, a prophylactic approach to COVID-19 using these drugs, which are well tolerated, clinically applied, or FDA-approved compounds, would be rational (). Importantly, treatments for emerging infections by targeting host cell pathways, rather than the infectious agent directly, or to complement antivirals with drugs that enhance host cell resistance mechanisms have thus become an active and promising therapeutic strategy. This strategy is even more important and urgent to be explored in the case of such potentially and suddenly pandemic virus family, as coronaviruses are.
Statements
Author contributions
KF contributed to the design of this study, drafted the manuscript, and drew figures relative to lipid rafts. SA contributed to the conception of the idea and drafted the manuscript and figure relative to coronavirus description. DP conducted a wide literature search and drafted the manuscript on the lipid rafts section. EI drafted the manuscript on the autophagy section. PM provided autophagy expertise, contributed to draft and revision of the manuscript, and concurred with the final version of the review. MG provided lipid rafts expertise, and contributed to draft and review the manuscript and to the organization of the review. AR conceived the idea, drafted and revised the manuscript, coordinated the activity, and concurred with the final version of the review. All authors contributed to the article and approved the submitted version.
Funding
The authors gratefully acknowledge the financial support obtained from the Italian Ministry of Health (to MG), grant PE-2013-02354961, and Peretti Foundation (to PM), grant 3603.
Acknowledgments
We thank Massimo Delle Femmine for his support with the figures.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmicb.2020.01821/full#supplementary-material
FIGURE S1Taxonomy of CoVs Classification scheme of some representative human (in red) and animal (in black) coronaviruses.Abbreviations: FCoV, feline coronavirus; TGEV, transmissible gastroenteritis virus; PRCV, porcine respiratory coronavirus; HCoV, human coronavirus; PEDV, porcine epidemic diarrhea virus; Ro-BatCoV, Rousettus bat CoV; PHEV, porcine hemagglutinating encephalomyelitis virus; MHV, mouse hepatitis virus; BCV, bovine coronavirus; SARS-CoV, severe acute respiratory syndrome coronavirus; Bat SARSr-CoV, Bat SARS-like coronavirus; MERS-CoV, Middle East respiratory syndrome coronavirus; BuCoV, bulbul coronavirus; PDCoV, porcine deltacoronavirus; BWCoV, beluga whale coronavirus; IBV, avian infectious bronchitis virus; TCoV, Turkey coronavirus.
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Summary
Keywords
coronavirus, lipid rafts, autophagy, SARS-CoV-2, drugs
Citation
Fecchi K, Anticoli S, Peruzzu D, Iessi E, Gagliardi MC, Matarrese P and Ruggieri A (2020) Coronavirus Interplay With Lipid Rafts and Autophagy Unveils Promising Therapeutic Targets. Front. Microbiol. 11:1821. doi: 10.3389/fmicb.2020.01821
Received
30 April 2020
Accepted
10 July 2020
Published
11 August 2020
Volume
11 - 2020
Edited by
Joseph Alex Duncan, The University of North Carolina at Chapel Hill, United States
Reviewed by
Maryam Dadar, Razi Vaccine and Serum Research Institute, Iran; Roberta Olmo Pinheiro, Oswaldo Cruz Foundation, Brazil
Updates
Copyright
© 2020 Fecchi, Anticoli, Peruzzu, Iessi, Gagliardi, Matarrese and Ruggieri.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Paola Matarrese, paola.matarrese@iss.it
†These authors have contributed equally to this work
This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology
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