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 Table of Contents  
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
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aihb.aihb_108_21

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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

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  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.

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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.

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