As with the Heart, How the Spike Protein May Induce a Fibrosis Feedback Loop in the Liver

Additional evidence of how repeated infections and Spike Protein exposures destroy major organs.

Mechanisms of severe acute respiratory syndrome coronavirus-2 disease-induced liver injury and their consequences at organ level (left). Severe acute respiratory syndrome coronavirus-2 cellular targets involved in liver damage (center and right). Various factors have been postulated to contribute to liver injury in the context of coronavirus disease 2019 (COVID-19), including direct cytotoxic effects, vascular changes, immunological and inflammatory responses associated with COVID-19, immune responses triggered by COVID-19 vaccination, and drug-induced liver injury. In the context of liver injury associated with COVID-19, the histological patterns encompass features such as steatosis (both macrovascular and microvascular), lobular necroinflammation, portal inflammation, and vascular pathology. At the cellular level, hypoxia, metabolic dysfunction-associated fatty liver disease, and concomitant hepatitis C virus infection, and the cytokine storm may upregulate the Angiotensin-converting enzyme-2 (ACE2), transmembrane serine protease 2 and furin expression in hepatocytes. Mitochondrial dysfunction has been affected directly by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection of hepatocytes which in turn may be connected to pre-existing inflammation and the adverse impacts of excessive and dysfunctional adipose tissue. In cholangiocytes, SARS-CoV-2 Leads to a decrease in the mRNA expression of Claudin-1 and downregulates the expression of hepatobiliary transporters, such as ASBT and the chloride channel CFTR. The ACE-2 expression in Kupffer cells is still controversial. Hepatic stellate cells appear do not express ACE2 in any activation state. Their activation is a pivotal event in the progression of chronic liver disease, as these cells serve as the primary source of fibrosis, and it is induced by proinflammatory and profibrotic signals, including angiotensin II, which is generated by the catalytic action of ACE as part of the profibrotic branch of the renin-angiotensin system. Liver and Kupffer cell are created with BioRender.com. ROS: Reactive oxygen species; ACE2: Angiotensin-converting enzyme-2; TMPRSS2: Transmembrane serine protease 2; MAFLD: metabolic dysfunction-associated fatty liver disease; ER: Endoplasmic reticulum; TGN: Trans-Golgi network.

I have repeatedly stated that, though initial infections and exposures to the Spike Protein may result in recoverable damage to major organs, repeated exposures may initiate a ROS feedback loop. This feedback loop may then inexorably progress to a state where the affected organs become a non-functioning fibrotic mass.

Indeed this has been proven.

In the heart:

Conclusion: Our data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.

The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice
https://pubmed.ncbi.nlm.nih.gov/36656778/

The lungs:

In the present study, we show that systemic delivery of the SARS-CoV-2-derived spike protein S1 elicits per se a progressive lung injury in mice, characterized by early endothelial cell dysfunction, leading to subsequent thrombo-inflammatory and fibrotic damage.

SARS-CoV-2 spike protein induces lung endothelial cell dysfunction and thrombo-inflammation depending on the C3a/C3a receptor signalling
https://www.nature.com/articles/s41598-023-38382-5#

The kidneys:

Perhaps the most interesting part of the study by Jansen and colleagues4 are the data obtained from human kidney organoids. This model has been used previously to assess responses to experimental COVID-19 therapies because human kidney organoids express ACE2 and transmembrane protease serine 2 (TMPRSS2) in proximal tubule-like structures. TMPRSS2 is necessary for priming of the spike protein of SARS-CoV-2 and subsequent viral entry into cells. Kidney organoids are readily infectable with SARS-CoV-2 and provide a model independent of haemodynamic or systemic factors to examine the impact of direct viral invasion on fibrosis. Kidney organoids infected with SARS-CoV-2 upregulated pro-fibrotic signalling pathways compared with uninfected organoids.

Potential SARS-CoV-2 kidney infection and paths to injury
https://www.nature.com/articles/s41581-022-00551-6

Now there is evidence showing this very same mechanism occurs in the liver.

Again, I cannot overemphasize how dangerous having ACE2 as a major receptor is.

REMEMBER: HIV infects CD4 cells. CD4 is found... on CD4 cells. ACE2 is EVERYWHERE.

Nevertheless, the pro-inflammatory environment instigated by direct or indirect injury to hepatocytes and cholangiocytes in the context of COVID-19 may establish conditions conducive to the activation of hepatic stellate cells, thereby initiating the process of fibrosis (Figure 1). This scenario may be particularly pertinent for individuals who have already underlying chronic liver diseases, such as MAFLD as a condition characterized by steatosis in > 5% of the liver parenchyma. While available data indicate that liver injury caused by COVID-19 is typically mild and temporary, long-term surveillance studies are essential to fully assess the possibility of hepatic fibrosis developing as a long-term effect of COVID-19, especially in patients with pre-existing liver diseases.

Yet, this is not the most important point. That would be the presence of Spike within these cells - the ORIGIN.

Nonetheless, certain researchers managed to demonstrate the presence of distinct coronavirus particles, including spike structures, within the cytoplasm of hepatocytes in individuals with COVID-19. These observations were accompanied by signs of mitochondrial swelling and apoptosis, suggesting a potential link between the virus and cellular damage in the liver. The diverse spectrum of histological injury patterns observed in individuals infected with SARS-CoV-2, including features such as macrovascular and microvascular steatosis, lobular necroinflammation, portal inflammation, and vascular pathology, likely emphasizes the intricate and multifactorial nature underlying abnormal liver test results in the context of COVID-19-associated liver injury.

Molecular mechanisms underlying SARS-CoV-2 hepatotropism and liver damage
https://www.wjgnet.com/1948-5182/full/v16/i1/1.htm

So, what we are facing is that repeated infections/exposures INDUCE/EXACERBATE these hepatic conditions. What is extant is made worse, what is healhy is made pathological.

And here. HERE IS THE MAIN POINT.

With repeated exposures and infections, how does the liver (or any other organ) have time to HEAL before the next onslaught begins?

I am continuing to research therapeutics to build A Mighty Fortress within our bodies to keep the Spike Protein at bay, limit damage, and allow our bodies to heal. Yet, with the virus becoming ever more transmissible... You see the dilemma? Still, I will continue to work and to have hope.

Thank you, always, for your kindness, generosity, readership and support.