The Interplay Between SARS-CoV-2 And The Endoplasmic Reticulum And The Resulting COVID-19 Symptoms And Long COVID Manifestations

COVID-19 News: The endoplasmic reticulum (ER) is a complex, interconnected network of channels and flattened sacs that plays a pivotal role in various cellular functions, including protein synthesis, folding, transport, and the regulation of intracellular calcium (Ca2+) levels. The ER has been identified as a critical player in the replicative cycle of SARS-CoV-2, the virus responsible for COVID-19. This article will explore the cytopathic effects of SARS-CoV-2 on the ER and its implications for the antiviral response of COVID-19 patients.


 
When SARS-CoV-2 infiltrates the ER, it commandeers the organelle for its own replication purposes, resulting in a stress response due to the accumulation of unfolded proteins in the ER lumen. This stress response, known as the Unfolded Protein Response (UPR), triggers a cascade of events that can lead to cell death via necroptosis, autophagy, and caspase-dependent apoptosis. Furthermore, it can activate mitogen-activated protein (MAP) kinase pathways, significantly impacting the patient's antiviral response.
 
The UPR can be instigated by an overload of viral proteins such as S, E, and M, which are frequently found in the ER. Additionally, the viral protein ORF8 has been shown to induce ER stress by activating inositol-requiring enzymes 1 (IRE1) and transcription factor 6 (ATF6) branches of the ER stress pathway. While doing so, it also functions as an interferon (IFN) antagonist, inhibiting IFNβ production.
 
Apart from the UPR, SARS-CoV-2 infection can cause severe ER membrane restructuring due to double membrane vesicle (DMV) formation during viral replication and ER membrane exhaustion resulting from continuous viral particle synthesis. The susceptibility of host cells to UPR depends on their pre-existing state. Factors such as age, comorbidities, immunosenescence, genomic instability, telomeric attrition, and inflammasome formation may predispose older COVID-19 patients to a poor prognosis.
 
SARS-CoV-2 is known to interact with multiple host proteins in the ER, affecting approximately 40% of the entire virus-host interactome. For instance, the SARS-CoV-2 M protein interacts with several ER proteins, such as reticulon 4 (RTN4), receptor expression-enhancing proteins 5 (REEP5), and 6 (REEP6). These interactions may influence ER morphology and IL-8-mediated responses, which play a role in olfactory dysfunction in COVID-19 patients.
 
Furthermore, nsp6 and ORF9c proteins of SARS-CoV-2 have been found to interact with Sigma receptors, transmembrane proteins located in the ER involved in numerous cellular functions. The alteration of these receptors could explain some of the symptoms of COVID-19 and Long COVID diseases, such as cognitive disorders, memory impairment, anxiety, depression, pain, and neurodegeneration which have been reported in past studies and COVID-19 News coverages.
 
The virus can also reconfigure the trafficking and structure of the ER through the interaction of its proteins with host cell proteins. For example, the SARS-CoV-2 nsp7 protein interacts with several ER-related host proteins, such as selenoprotein S (SELENOS), RAS oncogene family member 1 (RAB1A), mannosyl-oligosaccharide glycosidase (MOGS), cytochrome b5 reductase 3 (CYB5R3), and cytochrome b5 type B (CYB5B).
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These interactions could potentially alter the degradation of misfolded luminal endoplasmic reticulum (ER) proteins, vesicle trafficking from the endoplasmic reticulum to the Golgi apparatus, and protein glycosylation patterns .
 
Another interaction worth mentioning is between the SARS-CoV-2 ORF8 protein and some ER-related host proteins, such as endoplasmic reticulum lectin OS9 (OS9), lysyl oxidase (LOX), FKBP prolyl isomerase 7 (FKBP7), and ER degradation enhancer alpha-mannosidase-like protein 3 (EDEM3) [26]. Among these, OS9 and EDEM3 are ER-associated degradation-related (ERAD) proteins that play a crucial role in coronavirus-induced DMV formation.
 
These intricate interactions between viral and host proteins in the ER highlight the complex interplay between SARS-CoV-2 and the host cell machinery. The ER's cytopathic effects contribute to the pathophysiology of COVID-19 and may partially explain the varied clinical manifestations observed in infected individuals.

Understanding these molecular mechanisms can provide valuable insights for the development of targeted therapeutic interventions. For instance, the pharmacological targeting of Sigma receptors has been proposed as a potential therapy to alleviate the clinical deterioration associated with COVID-19 and Long COVID diseases. Moreover, further research on the direct effects of SARS-CoV-2 on ER morphology and IL-8-mediated responses may offer novel therapeutic avenues for mitigating olfactory dysfunction in COVID-19 patients.
 
In conclusion, the endoplasmic reticulum's role in the SARS-CoV-2 replicative cycle and its cytopathic effects on host cells is an area of great interest for researchers. Unraveling the complex interplay between viral and host proteins in the ER, along with understanding the implications of the UPR, could pave the way for the development of more effective antiviral therapies to combat COVID-19 and its long-term consequences. As our understanding of these processes advances, it is essential to continue exploring innovative therapeutic strategies that target the molecular mechanisms underpinning the devastating impact of SARS-CoV-2 infection on human health.
 
References:
 
The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles
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SARS-CoV-2 activates ER stress and Unfolded protein response
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Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy
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Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?
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Endoplasmic reticulum secretory pathway: Potential target against SARS-CoV-2
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The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta
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Endoplasmic Reticulum Stress in Elderly Patients with COVID-19: Potential of Melatonin Treatment
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A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
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Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival
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Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis
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Long COVID, neuropsychiatric disorders, psychotropics, present and future
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Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor
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Cytochrome b₅ reductase and the control of lipid metabolism and healthspan
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Identification of a novel chloride channel expressed in the endoplasmic reticulum, golgi apparatus, and nucleus
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Regulation of Integrin β 1 recycling to lipid rafts by Rab1a to promote cell migration
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Coronaviruses Hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication
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