The impact of SARS-CoV-2 Spike protein on microglial purinergic signaling

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Researchers from Universidade Federal do Rio de Janeiro-Brazil have in a new study discovered that SARS-CoV-2 spike protein alters microglial purinergic signaling.

The study findings were published as an abstract in the peer reviewed journal: Frontiers in Immunology. A detailed version of the study is expected to be published in coming weeks.
https://www.frontiersin.org/articles/10.3389/fimmu.2023.1158460/abstract

Microglia are immune cells that reside in the brain and play a critical role in maintaining brain homeostasis. Purinergic signaling is an important signaling pathway in microglia that modulates their activity.

Purinergic signaling involves the release and binding of extracellular purines such as ATP and adenosine to their receptors, which are expressed on the surface of microglia. This binding can trigger a cascade of intracellular signaling events that can modulate microglial activity and contribute to a variety of physiological processes, such as synaptic plasticity, inflammation, and cell death.

In microglia, purinergic signaling can be mediated by two main types of receptors: P2X receptors, which are ionotropic receptors that are activated by ATP, and P2Y receptors, which are metabotropic receptors that are activated by ATP and other purines such as ADP and UTP. These receptors are expressed in different subtypes and are involved in different downstream signaling pathways, which can have distinct functional consequences.

The modulation of purinergic signaling in microglia has been implicated in a variety of neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, epilepsy, and depression. Dysregulated purinergic signaling has been shown to contribute to neuroinflammation, neurodegeneration, and cognitive impairment.

Recent research has suggested that the SARS-CoV-2 spike protein can impact microglial purinergic signaling, as discussed in the previous response. This may contribute to the neurological symptoms that have been observed in some COVID-19 patients.

In this new study, the researchers have found that ….

Despite long-term sequelae of COVID-19 are emerging as a substantial public health concern, the mechanism underlying these processes still unclear.

Evidence demonstrates that SARS-CoV-2 Spike protein can reach different brain regions, irrespective of viral brain replication resulting in activation of pattern recognition receptors (PRRs) and neuroinflammation. Considering that microglia dysfunction, which is regulated by a whole array of purinergic receptors, may be a central event in COVID-19 neuropathology, we investigated the impact of SARS-CoV-2 Spike protein on microglial purinergic signaling.

Here, we demonstrate that cultured microglial cells (BV2 line) exposed to Spike protein induce ATP secretion and upregulation of P2Y6, P2Y12, NTPDase2, and NTPDase3 transcripts.

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P2Y6 is a metabotropic receptor that is activated by uridine nucleotides, and its upregulation has been shown to contribute to the inflammatory response in various cell types, including macrophages, epithelial cells, and endothelial cells.

P2Y12 is another metabotropic receptor that is activated by ADP and has been implicated in platelet activation and aggregation. Its upregulation in response to SARS-CoV-2 infection may contribute to the hypercoagulation and thrombotic events that have been observed in some COVID-19 patients.

NTPDase2 and NTPDase3 are ectonucleoside triphosphate diphosphohydrolases that are involved in the degradation of extracellular nucleotides such as ATP and ADP. Their upregulation may represent a compensatory response to the increased purinergic signaling that occurs in response to SARS-CoV-2 infection.

Metabotropic receptors are a class of cell surface receptors that are involved in modulating cellular signaling pathways in response to the binding of ligands such as neurotransmitters, hormones, and other signaling molecules. Unlike ionotropic receptors, which directly gate ion channels in response to ligand binding, metabotropic receptors work indirectly through G proteins and second messenger systems.

When a ligand binds to a metabotropic receptor, it activates an intracellular signaling cascade that can modulate a variety of cellular processes, such as gene expression, ion channel activity, and enzyme activity. These downstream effects are mediated by G proteins, which are trimeric proteins that can dissociate into alpha, beta, and gamma subunits when activated by a receptor.

The alpha subunit of the G protein can interact with various effector proteins such as adenylate cyclase, phospholipase C, and ion channels, resulting in the production of second messenger molecules such as cyclic AMP, inositol triphosphate, and diacylglycerol. These second messengers can then activate downstream signaling pathways that ultimately result in the desired cellular response.

Metabotropic receptors are involved in a wide range of physiological processes, including neurotransmission, hormone signaling, cardiovascular regulation, and immune function. Dysregulation of metabotropic receptor signaling has been implicated in various disease states, such as neurological disorders, cardiovascular disease, and cancer.

Overall, the complexity of metabotropic receptor signaling and the wide range of downstream effects it can modulate make it an important area of research in both basic science and clinical medicine.

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Also, immunocytochemistry analysis shows that spike protein increases the expression of P2X7, P2Y1, P2Y6, and P2Y12 in BV2 cells. Additional, hippocampal tissue of Spike infused animals (6,5ug/site, i.c.v.) presents increased mRNA levels of P2X7, P2Y1, P2Y6, P2Y12, NTPDase1, and NTPDase2.

Immunohistochemistry experiments confirmed high expression of the P2X7 receptor in microglial cells in CA3/DG hippocampal regions after spike infusion.

These findings suggest that SARS-CoV-2 Spike protein modulates microglial purinergic signaling and opens new avenues for investigating the potential of purinergic receptors to mitigate COVID-19 consequences.

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