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Long COVID: A new study by researchers from the Federal University of Rio de Janeiro- Brazil has found that various cognitive issues and impairment that is manifestated in Long COVID is actually caused by the SARS-CoV-2 spike protein that induces long-term TLR4-mediated synapse issues. The study has possible implicationa not only for those infected by the COVID-19 disease but also those exposed to the spike proteins via jabs!
The toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an intracellular signaling pathway NF-κB and inflammatory cytokine production which is responsible for activating the innate immune system.
TRL4 expressing cells are myeloid (erythrocytes, granulocytes, macrophages) rather than lymphoid (T-cells, B-cells, NK cells). Most myeloid cells also express high levels of CD14, which facilitates activation of TLR4 by LPS. It is most well known for recognizing lipopolysaccharide (LPS), a component present in many Gram-negative bacteria (e.g. Neisseria spp.) and selected Gram-positive bacteria. Its ligands also include several viral proteins, polysaccharide, and a variety of endogenous proteins such as low-density lipoprotein, beta-defensins, and heat shock protein. It should be noted that Palmitic acid is also a TLR4 agonist.
The ongoing COVID-19 pandemic has affected the global population in an unprecedented scale, with long-term consequences of SARS CoV-2 infection now emerging as a serious concern. Cognitive dysfunction is often reported in Long-COVID patients, but its underlying mechanisms remain unknown.
The study team demonstrated that brain exposure to SARS-CoV-2 spike (S) protein through its infusion into the lateral ventricle of adult mice induced late cognitive impairment, hippocampal synapse loss, and microglial engulfment of presynaptic terminals.
Additionally, TLR4 blockage prevented SARS-CoV-2-associated detrimental effects on memory in mice and TLR4 single nucleotide polymorphism (SNP) rs10759931 was associated with late cognitive outcome in mild COVID-19-recovered patients.
The study findings indicate that S protein directly impacts the brain and identify TLR4 as a key target to prevent cognitive dysfunction.
The Long COVID study team says that to their knowledge, this is the first animal model that recapitulates Long COVID cognitive impairment, opening new avenues for developing new strategies to prevent or treat the neurological outcomes of COVID-19.
The study findings were published on a preprint server and is currently being peer reviewed.https://www.biorxiv.org/content/10.1101/2022.06.07.495149v2
< ;p>To date, it has been discovered that Long COVID comprises a myriad of symptoms that emerge after the acute phase of infection, including psychiatric symptoms, and dementia-like cognitive dysfunction.
However, clinical studies have largely mapped the spectrum of neurological symptoms in Long-COVID patients, but do not provide significant advance in describing the molecular mechanisms that trigger this condition or targets for preventive/therapeutic interventions.
Many studies involving COVID-19 preclinical models have entirely focused on the acute impacts of viral infection. Therefore, it is mandatory to develop novel tools to dissect the mechanisms underlying the neurological deficits in long COVID, especially the direct effect of the virus and/or viral products on the brain.
Studies have suggested that the Spike protein can be released from virions suggesting that it could directly trigger brain damage. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693302/
The study team hence speculated that the spike proteins play a central role in neurological dysfunctions associated with COVID-19, independently of SARS-CoV-2 replication in the brain.
Past studies demonstrated that the hippocampus is particularly vulnerable to viral infections. Accordingly, brain scans of COVID-19-recovered patients showed significant changes in hippocampal volume, an important predictor of cognitive dysfunction in both normal aging and Alzheimer's disease.
The study team developed a rodent model that mimics key neurological features of long COVID through brain icv infusion of Spike proteins. Using two hippocampal-dependent behavioral paradigms, the study team found that brain exposure to Spike proteins disrupts long term mouse memory, with no early behavioral impact.
To the study team’s knowledge, this animal model is the first to recapitulate the late cognitive impact of COVID-19. Synapse damage is a common denominator in a number of memory-related diseases, often preceding neurodegeneration.
It has been shown that neuroinvasive viruses, such as West Nile virus (WNV), Borna disease virus (BDV) and Zika virus (ZIKV), are also associated with synapse impairment.
Likewise, the study team found that the late cognitive dysfunction induced by the spike protein was accompanied by prominent synapse loss in mice hippocampus.
New data have already revealed the upregulation of genes linked to synapse elimination in SARS-CoV-2-infected human brain organoids and in post-mortem samples from COVID-19 patients.
Similarly the study team found that infusion of Spike proteins into mouse brain induces a late elevation in plasma levels of NFL, an axonal cytoskeleton protein recently identified as a component of pre- and postsynaptic terminals.
Plasma NFL increase can be employed as a marker of synapse loss and disease progression in neurodegenerative diseases, including Alzheimer's disease.
Recent studies showed that plasma NFL levels are higher in patients with severe COVID-19 compared to healthy age matched individuals, as well as inversely correlated to the cognitive performance in COVID-19 patients, reinforcing the translational potential of the study team’s model.
These findings suggest that brain exposure to Spike proteins induces the synapse loss and behavioral alterations typical of viral encephalitis, leading to a prolonged neurological dysfunction that can persist long after recovery from the infectious event.
Microglia are the most abundant immune cell type within the CNS and play a critical role in most of the neuroinflammatory diseases. In viral encephalitis, microglial cells have both protective and detrimental activities depending on the phase of infection.
Past studies showed that human coronaviruses can reach the CNS and induce gliosis both in mature and immature brain tissues.
The study team found that microglial cell lineage BV-2 was impacted by Spike protein, corroborating recent data showing an increase in proinflammatory mediators in S1- stimulated microglia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551352/
As cultured primary cortical neurons were not directly affected by Spike protein stimulation, the in vitro results indicate that microglia could be seen as the main cell type affected by exposure to SARS-CoV-2 Spike protein. It is well known that viral infections are often associated with excessive activation of inflammatory and immune responses, which may in turn elicit and/or accelerate brain neurodegeneration.
Here, the study team found that Spike protein-infused mice presented late microglial activation, but not astrocyte reactivity, similar to observed in other animal models of viral encephalitis. Hippocampal increased levels of proinflammatory mediators were found only at late time points after Spike protein infusion, showing a temporal correlation with synaptic loss and cognitive dysfunctions.
Conversely, the study team found that the downregulation of IFNAR2 gene occurred shortly after Spike protein injection, similar to what is observed in neuronal cells of post-mortem COVID-19 patients. https://pubmed.ncbi.nlm.nih.gov/34153974/
This study finding corroborates recent evidence demonstrating that SARS-CoV-2 may evade innate immune through modulation of type-I IFN responses.
The study data show that brain exposure to Spike protein induces an early negative modulation of the main receptor involved in type-I IFN response followed by a late proinflammatory process in the hippocampus.
Importantly a complement-microglial axis has emerged as one of the key triggers of synapse loss in memory-related diseases.
The classical complement cascade, a central player of innate immune pathogen defense, orchestrates synaptic pruning by microglia during physiological and pathological conditions.
The study team had previously reported that hippocampal synapses are phagocytosed by microglia during ZIKV brain infection, in a process dependent on C1q and C3. https://www.nature.com/articles/s41467-019-11866-7
Another study showed hippocampal synapse loss in post-mortem samples of patients with WNV neuroinvasive disease, as well as complement-dependent microglial synapse engulfment in both WNV-infected and -recovered mice.
The study team from Brazil demonstrated that cognitive impairment induced by Spike protein is associated with hippocampal C1q upregulation and microglial engulfment of presynaptic terminals. Additionally, chronic C1q neutralization preserved memory function in Spike protein-infused mice, supporting the role of C1q-mediated synaptic pruning as an important mediator of long COVID cognitive impairment.
The pattern recognition receptor TLR4 has been implicated in the neuropathology of viral encephalitis classically associated with memory impairment, including those caused by WNV, Japanese encephalitis virus (JEV) and BDV, as well as age-related neurodegenerative diseases. https://www.frontiersin.org/articles/10.3389/fnins.2020.00444/full
Significantly, in silico simulations predicted that the Spike protein could be recognized by the TLR4, with this interaction activating the inflammatory signaling, independently of ACE2. https://pubmed.ncbi.nlm.nih.gov/32383269/
The study team found that a single brain infusion of Spike protein induced hippocampal TLR4 upregulation.
In order to gain further insight into the role played by TLR4 in COVID-19-induced brain dysfunction, the study team first performed the pharmacological blockage of TLR4 signal transduction early after Spike protein brain infusion. This strategy significantly prevented the long-term cognitive impairment observed in their model.
Likewise, late cognitive impairment induced by Spike protein was absent in TLR4-deficient mice, in accordance with previous findings in animal models of dementia.
Importantly, the study team also found that Spike protein-induced plasma NFL increase was dependent on TLR4 activation, as early TLR4 inhibition mitigated changes in NFL levels.
Together, the study findings strongly suggest that brain dysfunction in Long-COVID is associated to Spike protein-induced TLR4 signaling in microglial cells.
The engagement of complement and TLRs in signaling crosstalk has been proposed to regulate immune and inflammatory responses in neurodegenerative diseases.https://pubmed.ncbi.nlm.nih.gov/32391019/
It was also shown that TLR4 activation induces the upregulation of complement components in the mouse hippocampus . https://www.frontiersin.org/articles/10.3389/fnagi.2019.00279/full
Considering the role of complement activation in synaptic pruning, the study team hypothesized that TLR4 is the molecular switch that regulates microglial synaptic engulfment.
The study data showed that absence of TLR4 confers protection against Spike protein-induced microglial mediated synaptic pruning, reinforcing the notion that aberrant immunity activation disrupts synaptic integrity and leads to cognitive dysfunction following pathogenic insult.
Finally, and relevantly, the study team validated their pre-clinical findings by examining whether TLR4 genetic variants could be associated with poor cognitive outcome in COVID-19 patients with mild disease.
In a cohort of mild COVID-19 patients carrying the GG genotype of TLR4 -2604G>A (rs10759931) variant, the study team identified a significant association between this genotype and the risk for cognitive impairment after SARS-CoV-2 infection.
The G allele has already been associated with increased risk for different disorders with immunological basis, including cardiovascular diseases, diabetes-associated retinopathy, cancer and asthma.
However the A allele can affect the binding affinity of the TLR4 promoter to transcription factors, culminating in lower expression of this gene in the allele carriers.
The study findings suggest that the complex crosstalk between TLR4, complement system and neuroinflammation are important events that determines the development of neurological symptoms in long COVID patients.
The impact of long COVID emerges as a major public health concern, due to the high prevalence of prolonged neurological symptoms among survivors. Therefore, strategies designed to prevent or treat neurological long COVID symptoms constitute an unmet clinical need.
The study findings described a new animal model that recapitulates the long-term impact of the exposure to SARS-CoV-2 Spike protein on cognitive function.
The study team found that Spike protein-induced cognitive impairment triggers innate immunity activation through TLR4, culminating with microgliosis, neuroinflammation and synaptic pruning. The translational value of this model is supported by the correlation between increased plasma NFL and behavioral deficits, as well as by the association between TLR4 genetic status and SARS-CoV-2 cognitive outcomes of recovered COVID-19 patients.
The study findings open new avenues for the establishment of interventional strategies towards prevention and/or treatment of the long-term brain outcomes of COVID-19.
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