U.S. Study Reveals That SARS-Cov-2 ORF8 Triggers Inflammatory Response In Immune Cells Through Myd88 Independently Of The IL-17 Receptor
ORF8 Transduces Inflammatory Signaling In Monocytes And Macrophages Via MyD88 Independently Of The IL-17R
: In a new study conducted at the University of Pittsburgh, researchers have uncovered a crucial mechanism by which the SARS-CoV-2 virus induces inflammatory responses in immune cells. The study focused on a specific viral protein called open reading frame 8 (ORF8), which has been found to be associated with disease severity in COVID-19 patients.
The study team aimed to investigate how ORF8 mediates signals in macrophages and monocytes, two types of immune cells that play a critical role in the body's immune response against viral infections. Previous reports and COVID-19 News
reports suggested that ORF8 interacts with the IL-17 receptor complex, which is responsible for transmitting signals related to inflammation. However, IL-17 signals were thought to be limited to nonhematopoietic cells, which raised questions about the role of ORF8 in immune cells.
To unravel the mystery, the study team examined the expression of IL-17 receptor components in mouse and human macrophages and monocytes. Surprisingly, they found that IL-17 receptor subunit mRNA was undetectable in these immune cell populations from SARS-CoV-2-infected lungs. In contrast, ORF8 was found to significantly elevate the expression of target cytokines in both mouse and human immune cells.
Furthermore, the study revealed that the signaling triggered by ORF8 was independent of the IL-17 receptor pathway. Neutralizing antibodies against IL-17 receptor subunits did not affect ORF8-induced signaling, and cells lacking IL-17 receptor subunits still exhibited ORF8 activity. Instead, the study team discovered that the TLR/IL-1R family adaptor protein known as MyD88 was essential for ORF8 activity in immune cells. Notably, MyD88 is not required for IL-17 signaling, highlighting the distinct mechanism employed by ORF8.
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the MYD88 gene. The MYD88 gene provides instructions for making a protein involved in signaling within immune cells. The MyD88 protein acts as an adapter, connecting proteins that receive signals from outside the cell to the proteins that relay signals inside the cell.
In innate immunity, the MyD88 plays a pivotal role in immune cell activation through Toll-like receptors (TLRs), which belong to large group of pattern recognition receptors (PRR). In general, these receptors sense common patterns which are shared by various pathogens….pathogen-associated molecular pattern (PAMPs), or which are produced/released during cellular damage….damage-associated molecular patterns (DAMPs).
The findings of this study provide crucial insights into the intricate interplay between SARS-CoV-2 and the immune system. Understanding how the virus manipulates immune cell responses is vital for developing effective strategies to combat severe COVID-19 symptoms, particularly the cytokine storm…a hyperactive immune response characterized by excessive inflammation.
The study team also noted
that ORF8 is just one of many viral proteins that mimic cytokines, such as IFN and TNF, to evade the immune system. Although the exact advantage gained by the virus through ORF8 is yet to be determined, the study highlights the significance of exploring viral proteins that modulate immune responses.
Moreover, this research sheds light on the complex network of immune signaling pathways and challenges previous notions about IL-17 signaling in immune cells. While IL-17 was believed to primarily act on nonhematopoietic cells, this study suggests that myeloid cells, such as macrophages and monocytes, can also respond to IL-17 under specific conditions.
As the COVID-19 pandemic continues to affect millions worldwide, uncovering the mechanisms behind severe disease outcomes is of paramount importance. Targeting inflammatory cytokines, including those induced by ORF8, could pave the way for new therapeutic interventions to mitigate the devastating effects of the cytokine storm.
Further research is required to fully elucidate the function of ORF8 and its implications for modulating cytokine expression in immune cells. By unraveling the intricate interactions between the virus and the immune system, scientists can develop novel approaches to combat the severe consequences of SARS-CoV-2 infection. The University of Pittsburgh study serves as a crucial step forward in our understanding of COVID-19 pathogenesis and the development of potential therapeutic strategies.
The study findings were published in the peer reviewed journal: The Journal of Immunology.
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