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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 12  |  Issue : 2  |  Page : 114-119

The role of severe acute respiratory syndrome coronavirus 2 viroporins in inflammation


Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission15-Jul-2021
Date of Decision03-Dec-2021
Date of Acceptance03-Dec-2021
Date of Web Publication13-May-2022

Correspondence Address:
Jila Yavarian
Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aihb.aihb_108_21

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  Abstract 


In December 2019, genomic screening of clinical samples from patients with viral pneumonia in Wuhan, China, revealed the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is the official name for the disease caused by this virus, according to the World Health Organization. SARS-CoV-2 can activate the NLRP3 inflammasome directly in apoptosis-associated speck-like protein (ASC)-dependent or independent manner through several proteins, including viroporins. Viroporins are viral proteins with ion channel functions that play crucial roles in different aspects of virus replication and pathogenesis. SARS-CoV-2 viroporins encoded by Open Reading Frame (ORF) 3a, ORF8 and the E gene activate the NLRP3 inflammasome and trigger the cleavages of pro-interleukin 1 β (IL1 β) and pro-IL18 by the caspase enzyme and convert them to the mature form (IL-1 β, IL18). Most of the inflammation in severe COVID-19 patients is caused by the activation of inflammasomes. Studies revealed that SARS-CoV-2 viroporins could be the possible targets for therapeutic interventions.

Keywords: Coronavirus, inflammasome, severe acute respiratory syndrome-coronavirus 2, viroporins


How to cite this article:
Zebardast A, Latifi T, Yavarian J. The role of severe acute respiratory syndrome coronavirus 2 viroporins in inflammation. Adv Hum Biol 2022;12:114-9

How to cite this URL:
Zebardast A, Latifi T, Yavarian J. The role of severe acute respiratory syndrome coronavirus 2 viroporins in inflammation. Adv Hum Biol [serial online] 2022 [cited 2022 Aug 19];12:114-9. Available from: https://www.aihbonline.com/text.asp?2022/12/2/114/345203




  Introduction Top


In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered for the first time in Wuhan, China.[1] SARS-CoV-2 spreads quickly in China and other nations and caused an epidemic disease. As SARS-CoV-2 seriously threatened world health and claimed many lives, the World Health Organization declared COVID-19 as a pandemic on 11 March 2020.[2] The new coronavirus is a member of the Beta-coronavirus genus that shares similarities to SARS-CoV.[3],[4]

Host cells directly infected by SARS-CoV-2 and the virus replication cycle resulted in increased inflammatory responses by different mechanisms.[5],[6] Viroporins have different amino acid lengths, for example, Open Reading Frame (ORF) 3a is the largest accessory protein with 275 amino acids, but the E protein is a small envelope protein that is composed of 75 amino acids.[7],[8] Viroporins also contain highly hydrophobic domains that form an amphipathic alpha-helix.[9] While many viroporins are not needed for viral replication, their presence significantly boosts virus particle formation.[10],[11],[12],[13] They communicate directly with membranes and form pores to enhance the transport of ions and small molecules across cell membrane.[14],[15] Studies showed that viroporins have crucial roles in severe COVID-19 inflammations and prompt infected cells to death.[16],[17] Increased production of pro-inflammatory cytokines is the main cause of ARDS development, lung injury and death.[18],[19] In human primary monocytes, SARS-CoV-2 infection causes pyroptosis-induced lytic cell death, which may contribute to the increased inflammatory response and leukocytopenia seen in patients with severe COVID-19 infection.[20] In addition, the pathogenesis and pathophysiology of autoimmune disorders, infectious diseases and neurodegenerative diseases are all linked to abnormal inflammasome activation.[21] SARS-CoV-2 encodes three viroporins, including ORF3a, E and ORF8a, which can modify the permeability of the host cell membranes to facilitate viral assembly and release, and they are considered as virulence factors.[22] These viroporins can be the potential targets for antiviral therapies.[23],[24] In this review, we try to summarise the role of SARS-CoV-2 viroporins in COVID-19 inflammation.


  Severe Acute Respiratory Syndrome Coronavirus 2 Top


Coronaviruses are pleomorphic RNA viruses and belong to the nidovirales order, which comprises the cornidovirineae suborder that contains the coronaviridae family.[25] There are four genera of coronaviruses in the coronaviridae family known as alpha-coronaviruses, beta-coronaviruses, gamma-coronaviruses and delta-coronaviruses.[26] The novel beta-coronavirus has been reported in Wuhan, Hubei province, China and is called SARS-CoV-2. This virus causes coronavirus disease 2019 (COVID-19), a disease that may affect the lung tissue and airways.[27]

SARS-CoV-2 has a single-stranded positive-sense RNA genome that is approximately 30 kb.[28] It contains 29 ORFs that encode 16 non-structural (NSP1-NSP16), four structural including spike (S), envelope (E), membrane (M) and nucleocapsid (N) and nine accessory proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF9c and ORF10).[29],[30] The viral accessory proteins are involved in ion channel activity, morphogenesis, virus release and pathogenesis.[31]

SARS-CoV-2 encodes three viroporins, including ORF3a, E and ORF8a, which can alter the host cell membrane permeability to promote viral assembly and release. These viroporins can act as virulence factors by modifying the NOD-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasomes pathways. A dysregulated NLRP3 inflammasome activity by viral proteins can result in severe COVID-19 with tissue damage and a cytokine storm in patients with reduced immune fitness.[32] The cytokine storm is one of the pathological outcomes of this infection which occurs when the immune system overproduces inflammatory cytokines as a result of infection and a lack of negative feedback.[33] The inflammatory response in COVID-19 patients is an antiviral mechanism, but a powerful cytokine storm triggered by an unbalanced response can be very harmful to the patients. On the other hand, the overactivation of the immune response to SARS-CoV-2 infection can result in the severity of COVID-19.[34]


  Severe Acute Respiratory Syndrome Coronavirus 2 Open Reading Frame 3a Top


Enveloped viruses, like SARS-CoV-2, have viroporins inserted into membranes, and by transferring ions through membranes, they destroy chemoelectrical barriers.[35] ORF3a is the gene that encodes protein ORF3a, the largest of the three viroporins with 275 amino acids.[36] It has 72.4% sequence identity and 85.1% sequence similarity with the SARS-CoV ORF3a protein.[37] ORF3a is a multipass membrane protein that has two domains: a transmembrane domain (TMD) at the N-terminus and a cytosolic domain at the C-terminus (CM). ORF3a interacts with structural proteins S, E and M and facilitates virus spread by helping scatter membrane for cell lysis and virus release.[14],[38],[39] Furthermore, caveolin interacts with this protein, possibly controlling various stages of the viral cycle.[40] SARS-CoV-2 infection elicited strong CD4+ and CD8+ T cell responses against ORF3a in infected individuals.[41]

ORF3a contains a tumour necrosis factor receptor-associated factor 3-binding motif that activates the NLRP3 inflammasome and is a strong inducer of pro-IL1 β gene transcription.[42] This viral accessory protein activates the inflammasome in both ASC-dependent and independent modes by promoting IL-1β expression through NF-Kb.[43],[44] The inflammasome is a multiprotein complex that plays a role in inflammation. It regulates caspase-1 activation and processing of the pro-inflammatory cytokines IL-1 β and IL-18 during the innate immune response. The ORF3a protein of the SARS-CoV-2 primes and activates the inflammasome by effluxing potassium ions and oligomerising NEK7 and NLRP3.[16] Upon this oligomerisation, pro-caspase 1 will be recruited. The release of pro-inflammatory cytokines, including IL-1 β and IL18, is then mediated by caspase-1 [Dure 1].[43],[44]

An extraordinarily high level of inflammatory cytokines such as IL-1 β in severe COVID-19 patients characterises the increased immune response. An exacerbated immune response has been suggested as a major factor in these patients' poor outcomes.[45],[46],[47],[48] Higher SARS-CoV-2 infection and mortality rates are linked to mutations in the ORF3a protein.[37] Since ORF3a's ability to activate caspase-1, the main mediator of pro-inflammatory responses, is dependent on NLRP3, this pathway can be blocked in infected cells using a selective inhibitor of NLRP3 for therapeutic aims[16] [Table 1].
Table 1: Summary of severe acute respiratory syndrome-coronavirus-2 viroporins function in inflammation

Click here to view



  Severe Acute Respiratory Syndrome Coronavirus 2 Open Reading Frame 8 Top


SARS-CoV-2 ORF8 gene encodes two proteins, ORF8a with 39 aa and ORF8b with 84 aa.[53] The ORF8a protein in SARS-CoV2 human infected cells is the result of a 29-nt deletion in ORF8 that occurred after the virus crossed species.[54] The ORF8b protein strongly activates the NLRP3 inflammasome in macrophages and lung epithelial cells.[55] This protein interacts directly with the LRR domain of NLRP3 and forms cytosolic dot-like structures with NLRP3 and ASC, which causes cell death in macrophages similar to pyroptotic cell death [Figure 1].[55]
Figure 1: The role of SARS-CoV-2 viroporins in NLRP3 inflammasomes activation. The TRAF3-binding motif of the ORF3a can activate the NLRP3 inflammasome and promote the pro–IL1 β production. The ORF8b protein activates the NLRP3 inflammasome by interacting with the NLRP3. The E protein is another viroporin that promotes NLRP3 inflammasome activation and results in IL-1 β overproduction. Abbreviation: ACE2: Angiotensin-converting enzyme 2; PP: polyprotein; DMV: double-membrane vesicle; ERGIC: Endoplasmic Reticulum-Golgi Intermediate Compartment; ASC: Apoptosis-associated speck-like protein containing a caspase-recruitment domain; TRAF3: Tumour necrosis factor receptor-associated factor 3; ER: Endoplasmic Reticulum.

Click here to view


In SARS-CoV and SARS-CoV-2 infections, activating NLRP3 inflammasome pathways in patients cause acute respiratory distress syndrome and, eventually, death.[49] ORF8a also induces apoptosis through a mitochondrion-dependent pathway.[56] The full-length E and 3a proteins are essential for SARS-CoV replication and virulence, while viroporin 8a had only a minor impact on these processes.[23] Inhibition of the ORF8 function could be used as a tactic to increase SARS-CoV-2 surveillance and speed up eradication[57] [Table 1].


  Severe Acute Respiratory Syndrome Coronavirus 2 E protein Top


The E protein is the smallest of the main structural proteins in coronaviruses that are found on the viral envelope. This protein monomer can oligomerise to form a viroporin, which is an ion channel protein.[58] Besides viroporin activity, the E protein can participate in viral morphogenesis, assembly and budding.[59] The protein contains 74–109 amino acids and 8.4–109 kDa and has three regions: N-terminal negatively charged, TMD not recharged and C-terminal (CT) negatively charged.[60] It has several motifs, one of these motifs is a β-coil-β-motif which is a conserved proline residue in the CT region of the E protein and has a key role in the maturation and targeting of the protein in the Golgi. It has been shown that mutation in this residue prevents the assembly and release of virus particles.[61] A PDZ-binding motif (PBM) is another residue in the CT region of E protein with a critical role in pathogenicity by interactions with cell host factors such as the B-cell lymphoma extra-large protein, caenorhabditis elegans lin-7 protein 1 (PALS1); syntenin (an adaptor-like molecule with PDZ domains), sodium/potassium (Na+/K+) ATPase α-1 subunit, and stomatin with interfering in cell signalling.[62],[63]

In endoplasmic-reticulum–Golgi intermediate compartment (ERGIC) membranes, the SARS-CoV E protein forms protein-lipid channels that are permeable to calcium ions. This ion-channel activity promotes NLRP3 inflammasome activation and results in IL-1 β overproduction, which leads to immunopathological effects and worsens the disease [Figure 1].[52] Based on the GISAID database, from 4085 SARS-CoV-2 genomes, more than 40 amino acid mutations in the E gene were discovered. It shows the high mutation rates of the E gene.[50]

Several studies have been demonstrating that the interaction of E protein with host factors leads to increasing the virus pathogenicity. The interaction of E protein with PALSI disrupts tight junctions in the lungs and causes the SARS-CoV-2 to become more pathogenic than other coronaviruses.[64] Furthermore, the association of E with syntenin leads to the production of inflammatory cytokines that may contribute to tissue damage.[63] Given the critical role of E protein in virus assembly and pathogenicity, the E has the potential to be a target for antiviral therapy in COVID-19 patients, as some studies have shown that Gliclazide, Memantine and Retinol can inhibit E protein channel activity[45],[65] [Table 1].


  Viroporins Interactions Top


Protein-protein interactions are frequently used by viroporins and cellular IC proteins to cluster ICs at appropriate places in the cell.[66],[67],[68] PDZ domains and PBMs, peptide sequences that are most commonly found at the C terminus of IC proteins, mediate these interactions.[69],[70] During morphogenesis, the CT domain of the CoV E protein interacts with the viral membrane (M) protein. A PBM in the E protein sequence is important in interactions with cellular proteins and pathogenicity.[15] The interaction of protein 3a PBM with cellular PDZ proteins most likely results in a non-pathogenic signalling pathway for the host.[23] Furthermore, ORF7a and ORF3 may have a synergistic effect on ORF3 protein expression.[71] It has been discovered that these viroporins oligomerise and create holes during viral infections, disrupting normal physiological homeostasis in the host cell and so contributing to viral pathogenicity.[35],[42],[72] Two viroporins, the more dominant protein E and ORF3a, each with a PBM and IC activity, are essential for optimum viral replication in SARS-CoV. ORF3a and E are both needed for viral replication and pathogenicity.[23]

Several CoVs encode two viroporins,[73],[74],[75] including Middle East respiratory syndrome coronavirus, human coronavirus (HCoV)-229E, HCoV-OC43 and porcine epidemic diarrhoea virus, while SARS-CoV-1 and SARS-CoV-2 encode three proteins 3a, E and 8.[22],[23],[76],[77] Only three amino acid changes and one deletion distinguish the E protein of SARS-CoV-2 (T55S, V56F, E69R and G70-GAP) from SARS-COV-1.[78] When compared to the E protein of SARS-CoV, four mutations (including one deletion mutation) in the C-terminus of the SARS-CoV-2 E protein at positions 56, 57, 69 and 70 include an extra amino acid with an alkaline R group.[79] These mutations in the C-terminus of the SARS-CoV-2 E protein could disrupt the E protein's interaction with the host protein.[6] Regarding ORF3a, the sequence of the 3a protein was found to be 97.82% identical to the non-structural protein NS3 of the bat coronavirus RaTG13. SARS-CoV-2 ORF3a signature mutations cause isolates to cluster into established phylogenetic clades. Researchers discovered six functional domains (I to VI) in SARS-CoV-2. Virulence, infectivity, ion channel creation and virus release were all linked to the functional domains.[31] SARS-CoV-2 may encode an ORF8 protein that is similar in length to the full-length ORF8 seen in early SARS-Cov isolates, but its identity (32%) is significantly lower than that of the other proteins.[80]

Because many viruses have been discovered to have ion channels, inhibiting these proteins could be a promising avenue for antiviral medication development.[81] Only one class of chemicals, anti-flu aminoadamantanes, has been licensed as an antiviral medication so far.[82] In COVID-19 patients with cardiovascular illness, targeted suppression of the SARS-CoV-2 E viroporin can minimise the risk of sudden cardiac death and heart injury. Hexamethylene amiloride and amantadine, as well as their combinations, could be used to target the pentameric E protein channels.[77] Furthermore, ORF8 and ORF3a could be another promising therapeutic targets for disease treatment.[82],[83],[84] Inhibition of the ORF8 function could be used as a tactic to increase SARS-CoV-2 surveillance and speed up eradication.[85]


  Conclusion Top


SARS-CoV-2 accessory proteins such as ORF3a, ORF8 and structural E proteins are critical in COVID-19 pathogenesis by manipulating host immune mechanisms such as NLRP3 inflammasome pathways and producing inflammatory cytokines such as IL-1 β. Different COVID-19 studies around the world suggest that some viroporin inhibitors are thought to be equally efficient in blocking the SARS-CoV-2 viroporins. Effective treatment of cytokine storms, specifically in the 2nd week of disease, would necessitate both antiviral and anti-inflammatory strategies. However, to determine the antiviral activity of the various blockers and the dose-response characteristics of these viroporins for the tested inhibitors, more future in vitro and in vivo investigations will be required to improve the COVID-19 patients' outcomes.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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