Study Finds That Interleukin 27 Plays A Role In COVID-19 Pathogenesis and Inflammation Regulation

A new study by researchers from Universidad de Antioquia-Colombia has found that Interleukin 27 plays an important role in COVID-19 pathogenesis and inflammation regulation.


 
Interleukin 27 (IL27)
Interleukin 27 (IL27) is a heterodimeric cytokine, member of the IL6/IL12 family of cytokines, composed of IL27p28 and Epstein-Barr virus-induced 3 (EBI3) subunits.
 
Importantly, its interaction with a heterodimeric IL27Rα and Gp130 activates JAK-STAT signaling which plays critical role in the induction of the cellular response.
 
The Interleukin 27 or IL27 is expressed by antigen-presenting cells (APC) exposed to inflammatory stimuli that causes both pro-inflammatory and anti-inflammatory responses with diverse influence on the immune system.
 
It has been found that in monocytes, IL27 signals through STAT1, STAT3, and NF-kB, whereas in macrophages it signals through STAT1 and STAT3.
 
IL27 has received significant attention due to studies showing that IL27 suppresses replication of viruses including HIV-1, HBV, HCV, Influenza A virus (IAV), cytomegalovirus (CMV), and CHIKV.
 
Recently, it was reported that IL27 induces STAT1-depedent proinflammatory and antiviral response in CHIKV-infected macrophages through two signal pathways; an early signal dependent on recognition of CHIKV-PAMPs by TLR1/2-MyD88 to activate NF-κB, which in turn induces the mRNA expression of EBI3, and second signal dependent on the recognition of CHIKV replication intermediate (dsRNA) by TLR3-TRIF, to activate IRF1, which induces IL27p28 mRNA expression.
 
Both signaling pathways are required for the production of functional IL27 protein involved in the induction of ISGs, including AVPs, cytokines, CC- and CXC- chemokines, in an IFN-independent manner.
 
Interleukin 27 (IL27) And COVID-19
The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with a high mortality rate. The clinical course is attributed to the severity of pneumonia and systemic complications.
 
It has been found in COVID-19 patients and murine models of SARS-CoV-2 infection, the disease may be accompanied by over-exuberant production of cytokines, leading to accumulation of immune cells in affected organs such as lungs.
 
Past reports and COVID-19 News coverages have shown that SARS-CoV-2 infection antagonizes interferon (IFN)-dependent antiviral response, thereby preventing the expression of IFN-stimulated genes (ISGs). Lower IFN levels have been linked to more severe COVID-19.
 
Interleukin 27 (IL27) is a heterodimeric cytokine composed of IL27p28 and EBI3 subunits that induce both pro- and anti-inflammatory responses.
 
It has been found that IL27 also induces a strong antiviral response in an IFN-independent manner.
 
The study team investigated transcription levels of both IL27 subunits in COVID-19 patients.
 
The study findings showed that SARS-CoV-2 infection modulates TLR1/2-MyD88 signaling in PBMCs and monocytes, and induces NF-κB activation and robust pro-inflammatory response -dependent NF-κB-target genes expression, including EBI3; as well as it activates IRF1 signaling, that induces IL27p28 mRNA expression.
 
The study findings suggest that IL27 induces a robust STAT1-dependent pro-inflammatory and antiviral response in an IFN-independent manner in COVID-derived PBMCs, and Monocytes as a function of severe COVID-19 clinical course. Similar results were observed in SARS-CoV-2 Spike protein-stimulated macrophages.
 
Thus, IL27 can trigger host antiviral response suggesting the possibility of novel therapeutics against SARS-CoV-2 infection in humans.
 
The study finings were published on a preprint server and are currently being peer reviewed for publication into the journal: Archives of Virology (Springer)
https://www.researchsquare.com/article/rs-2514034/v1
 
Interleukin 27 or IL27, a cytokine with both pro- and anti-inflammatory functions, has been found to play a significant role in COVID-19 pathogenesis. The mRNA expression levels of IL27 subunits increase with the severity of the disease, suggesting it may be a useful marker for disease progression.
 
This cytokine may also serve as an alternative line of defense against viral infections, including SARS-CoV-2, through the induction of interferon-stimulated genes (ISGs) expression. IL27 may help regulate the host's inflammatory and antiviral response during SARS-CoV-2 infection, providing insights into potential therapeutic targets.
 
Studies have found that the mRNA expression levels of IL27 subunits (IL27p28 and EBI3) increase significantly with the severity of COVID-19. High levels of IL27 have been observed in both peripheral blood mononuclear cells (PBMCs) and monocytes of COVID-19 patients.
 
This finding is consistent with previous studies reporting increased IL27 levels in COVID-19 patients. IL27 may have a role in controlling SARS-CoV-2 infection through the expression of ISGs, which has not been previously studied or reported in the literature.
 
The IL27 signaling pathway is activated in response to SARS-CoV-2 infection, potentially altering the inflammatory response.
 
The TLR1/2-MyD88 signaling pathway may induce IL27 expression in response to SARS-CoV-2 infection, leading to a robust IL27-STAT1-dependent pro-inflammatory and antiviral response in COVID-19 patients. This hypothesis is supported by reports showing that TLR2 recognizes SARS-CoV-2 envelope and spike proteins to induce NF-κB-dependent pro-inflammatory responses. As the severity of COVID-19 increases, so does the expression of TLR1/2-MyD88 signaling components, NF-κB complex, and IRF1, which are consistent with the expression levels of IL27 subunits in COVID-19 patients. IL27 could play a novel host-defensive role to subvert viral inhibition of IFNs and may take over infection control.
 
Transcriptomic analysis of PBMCs and monocytes derived from COVID-19 patients and S-protein-stimulated macrophages derived from healthy individuals revealed that SARS-CoV-2 infection causes profound changes in the transcription program. This drives an unrecognized mechanism that induces an inflammatory response and acts in host antiviral response, which is IL27-dependent and IFN-independent.
 
Further research is needed to understand the mechanisms behind IL27 signaling's protective role against SARS-CoV-2 infection.
 
Conclusion
A transcriptomic analysis of COVID-derived PBMCs, monocytes, and SARS-CoV-2 S-protein-stimulated MDMs revealed significant increases in various gene expressions related to inflammation and antiviral responses. The study suggests that SARS-CoV-2 infection activates the TLR1/2-MyD88 signaling pathway, leading to a robust pro-inflammatory response, including IL27 production. IL27 can trigger a host antiviral response independently of IFN signaling, and the severity of the disease correlates with the response. Identifying innate antiviral immune factors that operate independently of IFN signaling may contribute to the development of new therapies against SARS-CoV-2 infection in humans.
 
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