BREAKING! Canadian Study Shows Cannabidiol Primes Innate Immune System, Increasing Responsive Readiness To SARS-CoV-2 Infection Without Activating Apoptosis!
: Researchers from the University of Waterloo-Canada have found in a new study that Cannabidiol or CBD primes innate immune system, increasing responsive readiness to SARS-CoV-2 infection without activating apoptosis! The discovery could mean that Cannabidiol or CBD could be deployed as a prophylactic towards SARS-CoV-2 infections pending more detailed studies.
The Cannabidiol (CBD)-SARS-CoV-2
study team primary objective was to study the effects on cellular innate immune responses to ORF8, ORF10, and Membrane protein (M protein) from the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, in combination with cannabidiol (CBD).
The study team used HEK293 cells that were transfected with plasmids expressing control vector, ORF8, ORF10, or M protein and these were assayed for cell number and markers of apoptosis at 24 h, and interferon and interferon-stimulated gene expression at 14 h, with or without cannabidiol (CBD). Cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) were also studied as a general model of RNA-type viral infection.
The study findings showed reduced cell number and increased early and late apoptosis were found when expression of viral genes was combined with 1–2 μM cannabidiol (CBD) treatment, but not in control-transfected cells treated with CBD, or in cells expressing viral genes but treated only with vehicle. In cells expressing viral genes, CBD augmented expression of IFNγ, IFNλ1 and IFNλ2/3, as well as the 2′-5′-oligoadenylate synthetase (OAS) family members OAS1, OAS2, OAS3, and OASL. CBD also augmented expression of these genes in control cells not expressing viral genes, but without enhancing apoptosis. Cannabidiol or CBD similarly enhanced the cellular anti-viral response to Poly (I:C).
The study findings demonstrate a poor ability of HEK293 cells to respond to SARS-CoV-2 genes alone, but an augmented innate anti-viral response to these genes in the presence of cannabidiol (CBD).
Hence cannabidiol or CBD may prime components of the innate immune system, increasing readiness to respond to RNA-type viral infection without activating apoptosis, and could be studied for potential in prophylaxis.
The study findings were published in the peer reviewed journal: Life Sciences.
The current ongoing COVId-19 pandemic caused by the rapid outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed almost 6.3 million lives globally.
Although COVID-19 vaccination has reduced the mortality rate and hospitalizations due to SARS-CoV-2 infection, the emergence of new variants of the virus has had the effectiveness of these vaccines decreased. Hence, more effective therapeutics and prophylactics are urgently needed to combat COVID-19.
Medical researchers have observed prominent homology in the genomic sequences of SARS-CoV-2 and SARS-CoV-1. The similarity in the genomes has helped researchers identify proteins and understand their function in disease manifestation. Ho
wever, the SARS-CoV-2 gene encodes for a novel protein, open reading frame 10 (ORF10), whose function remains largely unknown.
Researchers characterized this protein and found that ORF10 is associated with the suppression of innate immunity.
Importantly past studies revealed that ORF contained cytotoxic T lymphocyte epitopes!
Aside from ORF10, another SARS-CoV-2 gene that is not well understood is ORF8. Many studies have suggested that ORF8 is associated with evasion of host immune responses, initiation of endoplasmic reticulum stress, and development of cytokine storm via activation of the interleukin (IL)-17 pathway.
It has been found that type I IFN (IFNα and IFNβ) are the cytokines produced at the early stage of the infection and are involved in recruiting immunocytes that can inhibit viral replication. Type II IFN (IFNγ) activates neutrophils and macrophages, which can suppress virus replication. Type III IFN (IFNλ) stimulated genes (ISG) function as a downstream effector to induce apoptosis.
All these genes belong to the 2′-5′-oligoadenylate synthetase (OAS) family. However, activation of this pathway is weak in SARS-CoV-2, in contrast to SARS-CoV-1 and Middle East Respiratory Syndrome (MERS-CoV). A previous study has indicated that activation of the OAS-RNase L pathway could be an effective pharmacological strategy to suppress COVID-19 infection.
This study primarily focused on examining the effects of ORF8 and ORF10 genes and SARS-CoV-2 Membrane (M) protein on apoptosis. In addition, scientists further investigated the role of the aforementioned genes and SARS-CoV-2 M protein in the expression of IFNs and activation of downstream effectors.
Past studies have shown that ORF8 and ORF10 genes can suppress Type I and III IFN responses.
The study team evaluated the expression of these genes alone as well as in combination with cannabidiol (CBD).
Cannabidiol or CBD is a major non-psychotropic phytoconstituent isolated from Cannabis sativa and has been hypothesized as a therapeutic candidate against SARS-CoV-2 infection.
Many past studies have revealed that cannabidiol (CBD) possesses anti-inflammatory properties and can protect cells from metabolic stress associated with a viral infection.
The study team transfected HEK293 cells with plasmids expressing the control vector, ORF8, ORF10, or M protein, and the markers of apoptosis were determined after 24 hours.
The study team also evaluated IFN and IFN stimulated gene expression after 14 hours, with or without cannabidiol (CBD). The authors also studied cells transfected with polyinosinic:polycytidylic acid (Poly (I:C)) as a general model of RNA viral infection.
The study team observed a dose-dependent decrease in the number of cells per well when cells transfected with plasmids expressing ORF8, ORF10, or M protein, were treated with cannabidiol (CBD). However, similar findings were not observed in the absence of cannabidiol (CBD) treatment.
The study team reported that the expression of the SARS-CoV-2 genes ORF8, ORF10, and M protein alone could not induce apoptosis. This finding is in line with a past study that reported induction of apoptosis was absent in nasopharyngeal samples of COVID-19 patients.
This new study findings showed that apoptosis was lacking in the control group (without cannabidiol (CBD), in contrast, CBD augmented the induction of both early and late apoptosis in the treated group (with CBD).
Importantly this finding indicates that cannabidiol (CBD) can suppress viral infection by promoting the removal of infected cells.
The study team hypothesized that enhanced induction of IFN and ISG could be the reason for augmented apoptosis in the treated group.
The study findings showed that cannabidiol (CBD) regulates OAS family gene expression (OAS1, OAS2, OAS3, and OASL), which has been regarded as a powerful mediator of virus-related apoptosis. The study team reported that cannabidiol (CBD) augments the cellular antiviral response to Poly (I:C).
The study findings demonstrated that cannabidiol (CBD) enhances the antiviral innate immune response based on three SARS-CoV-2 genes, i.e., ORF 8, ORF 10, and M protein.
The study findings also indicate that cannabidiol (CBD) might prophylactically prime the innate antiviral response of cells to prepare them for a better antiviral response.
The study team stated that HEK293 cells alone were not fully able to respond to SARS-CoV-2 genes; however, when primed with cannabidiol (CBD), a superior immune response was observed.
The research findings imply that cannabidiol (CBD) may prime components of the innate immune system and enhance the preparedness of the cells to fight RNA-type viral infection without activating apoptosis. Therefore, in the future, this compound could be considered a potential therapeutic agent against SARS-CoV-2 infection.
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