How is a brick like a bat?
2012 Checklist: Achieving a good effector system to target / transfect / kill cells
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This checklist, published in 2012, describes how to achieve a good effector system to target / transfect / kill cells. Notwithstanding the natural emergence of Covid-19 from bat caves and marketplaces.
Cartoon: Copyright Gary Larson, FarSide
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2012: Achieving a good effector system [to target and kill cells]
Which of the following sounds familiar?
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The above table (also transcribed below) appears in an appreciated article from 2012,
Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression; “A Tight Partnership—Was Warburg Correct?”
Elliott RL and Head JF. 2012. DOI: 10.4236/jct.2012.34039
Note: I have added brackets and italics to [tumor], and suggest an abstract poetic exercise in reading this as [tumor or other cells]
Achieving a Good Effector System
A. “Identify [tumor] specific antigens
B. Upgrade these antigens:
1. CPG/DNA
2. Antisenses
3. Heat shock proteins (HSP)
4. Deliver more antigens by tumor targeting
a. Transferrin targeting technology
i. Slow cell death→release HMGB1→help pre-existing immunity-promote mobilization of calreticulin to [tumor] cell surface
b. Nanoparticles
c. Monoclonal antibodies
d. Xenogenization (selectively make [cancer] an autoimmune disease)
5. Make [tumor] more immunogenic by combination therapy with chemotherapy and radiation (time very important)
a. (HMGB1) release→TLR4→induce TLR dependent immunity (chloroquine may help this response) [See below for links regarding TLR4]
C. Use vaccine with appropriate antigens and good biological adjuvant
D. Intradermal injection at lymph node bearing area [femoral triange (intradermal better than subcutaneous)]
E. Ensure maturation of APCs (slow release of GM-CSF) and IL-12 also create pre-existing immunity
F. Test for proper T-cell activation (LBA)
G. Expand effector T-cell population (?IL-2)
H. Get CTLs to the [tumor] sites
1. Might be able to target CTLs to specific tumor site (ideas?) bite technology?
2. This would be enhanced by HSPs, some cytokines, acute inflammation (CPG/DNA), turn on the innate immune system
All of the above are intertwined and very related.”
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Below: Effector components from the list above related to today’s situation. Ideally this list will be reorganized to have links to each item, but time is a limited resource. Several list items are covered in my other posts and thoroughly by other Substack authors; for brevity, a start with 2 topics to get it posted.
Effector B.3: Heat Shock Proteins (HSP)
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SARS-CoV-2 and Guillain-Barré syndrome: molecular mimicry with human heat shock proteins as potential pathogenic mechanism.
Lucchese G, Flöel A.Cell Stress Chaperones. 2020 Sep;25(5):731-735. doi: 10.1007/s12192-020-01145-6.
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Covid-19, heat shock proteins, and autoimmune bullous diseases: a potential link deserving further attention
Kasperkiewicz M. Cell Stress Chaperones. 2021 Jan;26(1):1-2. doi: 10.1007/s12192-020-01180-3.
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Kasperkiewicz 2021: “A link between Covid-19 and development of autoimmunity has been reported. A possible explanation could be molecular mimicry between SARS-CoV-2 and human proteins. Peptide sharing has been found between antigenic epitopes of this virus and heat shock proteins (Hsp) 60 and 90, both of which are associated with autoimmune diseases including those of the bullous type. In particular, there is evidence for the latter Hsp acting as a pathophysiological factor and treatment target in autoimmune blistering dermatoses. Considering multimodal anti-inflammatory mechanisms of action of anti-Hsp90 treatment and drug repositioning results, it may be hypothesized that Hsp90 inhibition could also be a treatment option for cytokine storm-mediated acute respiratory distress syndrome in Covid-19 patients. Hence, although Covid-19-induced autoimmune bullous diseases have not been described in the literature so far, the potential relationship between Covid-19, Hsp, and these autoimmune disorders deserves further attention with respect to both pathophysiology and treatment.”
……..
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A deeper exploration of this point in my posts:
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Effector B.5: Make cells more immunogenic —> TLR4
fight bricks with bricks
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In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs
Choudhury A, Mukherjee S. J Med Virol. 2020;92:2105–13.
“The present study supported the zoonotic origin of SARS-CoV-2 from a bat and also revealed that TLR4 may have a crucial role in the virus-induced inflammatory consequences associated with COVID-19. Therefore, selective targeting of TLR4-spike protein interaction by designing competitive TLR4-antagonists could pave a new way to treat COVID-19.”
“We… found that cell surface TLRs, especially TLR4 is most likely to be involved in recognizing molecular patterns from SARS-CoV-2 to induce inflammatory responses.”
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Effector B.4.a: Transferrin targeting technology
“Transferrin Receptor is another receptor for SARS-CoV-2 entry” (Tang X et al., held in preprint since 2020, https://doi.org/10.1101/2020.10.23.350348)
“The role of transferrin receptor 1 (TfR1) in SARS-CoV-2 infection has received little attention;” “Ferristatin II Efficiently Inhibits SARS-CoV-2 Replication in Vero Cells” (Sokolov et al. 2022, DOI: 10.3390/v14020317)
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See my posts:
Articles cited here are for non-commercial education or research only and may be copyrighted.