Updated: 12th May ‘22

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Summary: pseudouridines in mRNA transfection agents can lead to the downregulation of certain toll like receptors, including TLR4...which is yet another tumor suppressor.

Clinical and immunological effects of mRNA vaccines in malignant diseases (2021)

Modulation of mRNA immunogenicity

“While improved immune activation can be of interest in vaccination strategies and might even replace adjuvant application, innate immune sensing can also create an unfavorable environment for the translation of mRNA vaccines and thus limit antigen expression [45, 128, 129]. Some naturally occurring modified nucleosides have been reported to diminish TLR activation when incorporated into the transcript [63]. One such example are pseudouridines, which aim at suppressing RNA-mediated immune activation while improving the translational capacity and stability of the RNA [128]. Although this process significantly improves expression of intra- and extracellular proteins and reduces the immune response, a residual induction of IFN1 and proinflammatory cytokines remains."

https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-021-01339-1

The role of toll-like receptor 4 in tumor microenvironment (2017)

Abstract

Tumors are closely related to chronic inflammation, during which there are various changes in inflammatory sites, such as immune cells infiltration, pro-inflammation cytokines production, and interaction between immune cells and tissue cells. Besides, substances, released from both tissue cells attacked by exogenous etiologies, also act on local cells. These changes induce a dynamic and complex microenvironment favorable for tumor growth, invasion, and metastasis. The toll-like receptor 4 (TLR4) is the first identified member of the toll-like receptor family that can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMPs). TLR4 expresses not only on immune cells but also on tumor cells. Accumulating evidences demonstrated that the activation of TLR4 in tumor microenvironment can not only boost the anti-tumor immunity but also give rise to immune surveillance and tumor progression. This review will summarize the expression and function of TLR4 on dendritic cells (DCs), tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), tumor cells as well as stromal cells in tumor microenvironment. Validation of the multiple role of TLR4 in tumors could primarily pave the road for the development of anti-tumor immunotherapy.

Keywords: TLR4, immune cells, tumor cells, tumor microenvironment

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5630445/

Also a big hat tip to the kiwi doctor:

To get it into the cells the mRNA has been altered and instead of Uridine in the genome base pair Pfizer have used a synthetic Uridyl molecule. It appears that this has radically altered how the mRNA works and has given it the ability to turn off Toll receptors 3,4, and 7. Toll receptor 4, TLR4, is one of our tumour suppressor agents and turning it off appears to be leading to the recurrence of cancers otherwise in remission, and in the appearance of aggressive, dense and unusual tumours, including deep melanomas and uterine cancers. The switching off of the other Toll receptors also appears to seriously compromise the innate immune system such that old latent viruses can reappear, such as herpes simplex, Zoster, HPV, (one pathologist in the US has already noticed an increase in abnormal Cervical smear tests) and even rabies. 50% of vaccinees have a lymphopenia (reduced white cell count) for up to 2 weeks post injection, leaving them vulnerable.

https://thebuzz.nz/a-kiwi-doctor-explains-why-they-wont-get-the-covid-vaccine/

#immunodeficiency #immunosuppression #cancer

Differences in Vaccine and SARS-CoV-2 Replication Derived mRNA: Implications for Cell Biology and Future Disease

Abstract

Codon optimization describes the process used to increase protein production by use of alternative but synonymous codon changes. In SARS-CoV-2 mRNA vaccines codon optimizations can result in differential secondary conformations that inevitably affect a protein’s function with significant consequences to the cell. Importantly, when codon optimization increases the GC content of synthetic mRNAs, there can be an inevitable enrichment of G-quartets which potentially form G-quadruplex structures. The emerging G-quadruplexes are favorable binding sites of RNA binding proteins like helicases that inevitably affect epigenetic reprogramming of the cell by altering transcription, translation and replication. In this study, we performed a RNAfold analysis to investigate alterations in secondary structures of mRNAs in SARS-CoV-2 vaccines due to codon optimization. We show a significant increase in the GC content of mRNAs in vaccines as compared to native SARS-CoV-2 RNA sequences encoding the spike protein.  As the GC enrichment leads to more G-quadruplex structure formations, these may contribute to potential pathological processes initiated by SARS-CoV-2 molecular vaccination.  

Introduction

The simplification of scientific jargon in the realm of public health can lead to the construction of a false consensus. One such over-simplification exists in our discussions surrounding the expression of SARs-CoV-2 spike protein in mRNA vaccines. This spike protein is often referred to as being bio-equivalent to the naturally expressed spike protein in SARs-CoV-2. Accordingly, it is suggested that this "may” constitute a safer immunological exposure as the rest of the genes responsible for replication of the virus are omitted. This often leads one to assume that the pathologies that arise from vaccine expressed spike protein should be a subset of those you might experience with the full-length live virus. The mRNA vaccines have the benefit of being a non-replication competent immune exposure, but are the spike proteins truly equivalent?

In this line of questioning, one must ask what is the purpose for codon optimizing a viral mRNA that is already adapted to its host? This does not come risk free. The potential dangers of codon optimization have been raised for in vivoapplications 1. Even synonymous codon changes incorporated into mRNA vaccines can alter the expected encoded protein conformation as the translation speed and efficiency can result in different protein folding. Despite identical amino acids, the altered conformation can function differently as compared to synonymous codon replacements of native mRNAs that have been put in place under the selective pressure of evolution of parasite-host adaptation. Codon optimization strategies for the development of mRNA vaccines can result in immune de-regularities, affect epi-transcriptomic regulation, and can lead to disease progression 1 2.

https://anandamide.substack.com/p/differences-in-vaccine-and-sars-cov?s=r

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