LATEST! Researchers Find That Dysregulated Cell Signaling As A Result Of SARS-CoV-2 Infection Contributes To Disease Severity.
: A new study has found that SARS-CoV-2 mediated dysregulation in cell signaling events are actually driving COVID-19 severity.
In a normal setting, in order to eradicate the illness, an immune response balanced against an unknown pathogen is essential.
Typically, a cascade of cell signaling events is immediately activated upon sensing the presence of SARS-CoV-2 by cellular toll like receptors in a natural host response manner against the invading virus. The ultimate aim of such innate immune signaling pathways is to provide a required level of protection to our bodies by interfering with the invader.
However, if there is any loss in such balance, an impairment in the immune system emerges that fails to control the regulated transcription and translation of signaling components.
As a result, excessive levels of proinflammatory mediators are released into the circulatory systems that ultimately causes “cytokine storms” and COVID-19 pathological syndromes. The limited production of interferons (IFNs), while excessive yield of pro-inflammatory cytokines followed by SARS-CoV-2 infection suggests an abnormal cell signaling event and explains the reasons of increased immunopathology and severity in COVID-19.
The SARS-CoV-2 Research
was conducted by researchers from Noakhali Science and Technology University-Bangladesh and Chittagong Medical University-Bangladesh.
The study findings were published in the peer reviewed journal: Virus Research.
The key findings of the study are:
-The TLRs and proximal signaling components are activated by SARS-CoV-2 infection.
-Uncontrolled activation of NF-κB, whereas, a limited and delayed IFN induction may support increased viral replication with excessive pro-inflammatory cytokine secretion.
-The activated NF-κB acts as a priming step for NLRP3 inflammasome formation and subsequent cell death in severe cases.
-A number of underlying but dysregulated cellular components accelerate the pathogenesis.
In the human host, when cellular toll-like receptors (TLRs) detect the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a sequence of cell signaling events is quickly triggered as part of the body's natural defense mechanism in response to the infecting virus.
If there is a loss in this equilibrium however, the host immune system becomes impaired and cannot maintain properly controlled transcription and translation of signaling components.
When this happens, the circulatory systems release an excessive amount of proinflammatory mediators, which eventually leads to what is called a "cytokine storm" and also causes numerous COVID-19 clinical disorders.
It was found that the SARS-CoV-2 infection is then followed by low levels of interferons (IFNs) and high levels of pro-inflammatory cytokines, which reflects an aberrant cell signaling event and explains the causes for enhanced pathogenicity and severity of COVID-19.
The study team
listed the typical clinical manifestations of COVID-19 due to dysregulated cell signaling pathways such as:
- Respiratory manifestations:
The often-common signs of COVID-19 respiratory problems include hypoxia, pneumonia, lung edema shown as acute lung injury (ALI), and acute respiratory disease syndrome (ARDS), which can typically result in lung failure. Diffuse alveolar destruction and increased endothelial and epithelial cell permeability, fluid leaking into the pulmonary interstitium, and severe disruption of gas exchange are the main pathological alterations seen in such patients. The production of various common inflammatory cytokines, such as interleukin (IL)-1-beta, IL-6, IL-8, IL-18, and tumor necrosis factor (TNF)-alpha, are strongly linked to the onset of these condition.
- Neurological manifestations:
Headaches, anosmia and ageusia are the most conspicuous neurological symptoms of COVID-19, with a further potential link with stroke, impaired consciousness, encephalopathy, and seizure. The SARS-CoV-2 coronavirus's impact on human nerve cells increases the likelihood that the virus will be able to pass through the blood-brain barrier (BBB) and invade the central nervous system (CNS). IL-1 and IL-6 can increase neuroinflammation by crossing the BBB, which can facilitate the penetration of virus-infected monocytes and peripheral white blood cells.
- Cardiovascular manifestations:
It has been found that when the SARS-CoV-2 coronavirus infects cardiac cells, the expression of the angiotensin-converting enzyme-2 (ACE-2) receptor can boost the recruitment of adaptor proteins necessary for the activation of inflammatory signaling pathways, which may lead to the generation of inflammatory cytokines. As a result, a variety of heart problems can develop, including myocarditis, a lack of contractile function, destruction to the cardiomyocytes, and the production of markers of cardiac injury that can eventually cause ischemia, coagulation, vascular inflammation, and thrombosis.
- Renal issues:
SARS-CoV-2 infections have furthermore been linked to acute renal damage and kidney function decline ( commonly referred to as acute kidney injury or AKI) as well. A serious issue with AKI has been identified in hospitalized individuals with severe COVID-19. Although there is no association found with SARS-CoV-2, the viral infection in the kidney is thought to trigger TLR4 mRNA in tubular cells that induce ischemia, tubular necrosis, and inflammation. The kidney is a direct target for SARS-CoV-2-related pathogenesis due to ACE2 expression on kidneys, adhesion of platelets with fibrin in peritubular capillaries, neutrophil recruitment induced by the complement, TLR stimulation, or Nod-like receptor protein 3 (NLRP3) inflammasome formation.
The study team also collated the major biomarkers of abnormal cell signaling events as follows:
: Increased levels of IL-6 appear to increase C-reactive protein (CRP) levels, disrupt T cell function, and decrease albumin, transferrin, and fibronectin synthesis.
: Furthermore, a poor COVID-19 prognosis is often observed in the presence of cytokine overproduction. In severe COVID-19 cases, the serum TNF-alpha level is excessively high, which has pro-inflammatory effects on its activity. The poor prognosis of COVID-19 is believed to be related to the rising serum levels of this cytokine, which is comparable to those of SARS and Middle East respiratory syndrome (MERS).
: The IL-1 family of cytokines is the main inflammatory cytokines generated by inflammasome activation accompanied by NF-B induction. Increases in IL-1 are significantly linked to COVID-19 severity.
- Caspase-1 and GSDMD
: Casp1p20, a proteolytically activated caspase-1, promotes the activation of substrates such as the inflammatory cytokines IL-1-beta, IL-18 as well as gasdermin-D and has been consistently found in the serum of COVID-19 patients as well as SARS-CoV-2-infected macrophages and monocytes. Therefore, in severe COVID-19, the identification of active caspase-1 is a key biomarker.
: Lactate dehydrogenase is released from damaged cells and is thought to be a possible indicator of vascular permeability in lung injury mediated by the immune system. Increased odds of having severe COVID-19 disease were connected with higher levels of lactate dehydrogenase (LDH).
: The detection of LPS (lipopolysaccharide) in the plasma of COVID-19 patients is quite common as secondary bacterial infection can be occurred in SARS-COV-2 infected lung. The LPS has the potency to induce TLRs and downstream NF-κB pathway activation. Past research data shows that high lipopolysaccharide (LPS) levels in the circulation have a correlation with severity of COVID-19 since the LPS has been seen to interact with SARS-CoV-2 spike protein and boost the inflammatory responses. So, the detection of LPS could be considered a useful biomarker in severe COVID-19 patients.
: C-reactive protein is a non-specific acute phase protein produced by hepatocytes that can increase in response to infection and inflammation, thus it become a biomarker for confirming different viral or bacterial infections. In COVID-19 diagnostics, CRP also has been suggested inconsistently as a prognostic marker, since, elevated level of CRP for patients with COVID-19 was associated with increased inpatient mortality and was indicative of disease severity at admission.
: Elevated level of D-dimer, a fibrin degradation product has been constantly detected in COVID-19 cases in severe stage.
: Increasing level of creatinine, an indication of kidney infection also reported to found in patients with COVID-19.
The study findings demonstrated the types of clinical outcomes resulting from the dysregulation of cellular signaling pathways as well as the key cellular components involved in the stimulation of imbalance and disease severity.
The study team concluded, “We could hypothesize that in spite of protective function in immunity, a loss of balance in cell signaling events could accelerate excessive inflammation due to dysregulated activation of NF-κB, mostly upon TLR-MYD88 induction, whereas, a limited and delayed TRIF-IFN induction seems to support increased viral replication. Moreover, in addition with upstream signaling dysregulation, the evidence of inflammasome specks formation and inflammasome induced severe pathophysiology suggests a dysfunctional immunological state of those patients whose immune system are pre-occupied by mitochondrial damage, telomere shortening, impaired adipocyte function, abnormal neutrophil activities and so on.”
The study team suggests that strategies should be taken by considering either the physiological and immunological state of the patients and stage of the disease to compensate the abnormalities. The selection of therapeutics should consider not only to antagonize the downstream soluble mediators (IL-6, IL-1 or other cytokine), but also to counteract upstream pathways by targeting potential TLRs that have direct interaction with the PAMPs or suppress the nuclear translocation of cytoplasmic transcription factors especially NF-κB.
A more detailed analysis however is still needed to understand the impact of TLRs or proximal accessory signaling molecules in response to SARS-CoV-2 infection and pathogenesis.
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