TLR3 Agonists like Ampligen: LL-37

[mitoMAN]

TLR3 Agonist might be an interesting treatment approach.
They improve TLR3 recognition of Virals and thus Interferon production.

AMPLIGEN is marketed in Argentinia for very severe ME/CFS Patients.
I read it costs about 42 000$ per year - so no real option.
There seems to be no other marketed medication as TLR3 Agonist so far.
https://me-pedia.org/wiki/Ampligen

https://me-pedia.org/wiki/Toll-like_receptor_3

Ampligen is a TLR3 agonist.[1] It stimulates the production of toll-like receptor 3 (TLR3), which is a naturally occurring protein. TLR3 recognizes the dsRNA present in some viruses, such as retroviruses, and stimulates a series of biochemical reactions that result is an increase in the production of interferon. Interferon, an important player in the body's immune system, protects against viral infections and activates immune cells, such as natural killer cells (NK cells).

List of TLR Receptors and their mechanics:
https://me-pedia.org/wiki/Toll-like_receptor


PLEASE fell free to post a list of known TLR-3 Agonists (even research ones)


However there seem to be other affordable TLR-3 Agonists on the market.

The Peptide LL-37 has been on the market for quite some time. It is a peptide occuring in the human body but can be syntheticly produced and administired.



LL37 and Cationic Peptides Enhance TLR3 Signaling by Viral Double-stranded RNAs
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026632
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0026632&type=printable

LL37 is a human cationic antimicrobial peptide that enters cells to act on multiple TLRs [18], [19], [20], [21]. It is released primary from neutrophils [22] and is cleaved from the C-terminal portion of hCAP-18 by proteinase 3. Improper levels of LL37 are associated with chronic respiratory diseases [23] and autoimmune diseases such as psoriasis [24], [25], [26]. Intriguingly, LL37 interacts with several classes of TLR ligands to modulate signaling by various TLRs. It can complex to bacterial lipopolysaccharide (LPS) to prevent activation of TLR4 [27], to single-stranded (ss) DNA to enhance signaling by TLR9 [25], [27], and to ssRNA to enhance signaling by TLR7 and 8 [26]. LL37 can also synergize with flagellin to regulate TLR5 and with PAM3CSK4 to modulate TLR2/1 [28]. At higher concentrations (5 to 10 µM), LL37 induces IL6 production in transformed human bronchial epithelial cells [29]. Most relevant to the present study, LL37 can act in concert with the TLR3 agonist poly(I:C) to increase IL8 and or IL6 production [28]. It is not clear how LL37 enhances TLR3 signaling, although Filewood et al [28] observed significant cytotoxicity that accompanied the enhancement of poly(I:C) signaling by LL37.


Conclusions/Significance: LL37 and several cell-penetrating peptides can enhance signaling by TLR3 and enable TLR3 to respond to viral dsRNA.

I am honestly not fit enought to ounderstand all mechanics within this article.
Maybe someone else can chim in?






Other studies on Influenza etc.

Human cathelicidin peptide LL-37 as a therapeutic antiviral targeting Venezuelan equine encephalitis virus infections
https://www.sciencedirect.com/science/article/abs/pii/S0166354218306818

Highlights
Host defense peptide LL-37 is presented as an approach to treating Venezuelan equine encephalitis virus (VEEV) infection.
LL-37 exhibits robust antiviral activity with minimal toxicity.
LL-37 is found to inhibit virus entry.
LL-37 modulates type I interferon (IFN) expression in infected host cells, thereby eliciting an antiviral state.

Antiviral Activity and Increased Host Defense against Influenza Infection Elicited by the Human Cathelicidin LL-37
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025333

vitro and in vivo experiments suggested that the peptides may act directly on the influenza virion rather than via receptor-based mechanisms. Influenza virus-infected mice treated with LL-37 had lower concentrations of pro-inflammatory cytokines in the lung than did infected animals that had not been treated with cathelicidin peptides. These data suggest that treatment of influenza-infected individuals with cathelicidin-derived therapeutics, or modulation of endogenous cathelicidin production may provide significant protection against disease.

On a sidenote, LL-37 seems to modulate Mast-Cell recognition as well.

Cathelicidin LL-37 Affects Surface and Intracellular Toll-Like Receptor Expression in Tissue Mast Cells
https://www.hindawi.com/journals/jir/2018/7357162/

 

[pattismith]

the question is: do we want to activate or antagonize TLR receptors in the brain,

I have read many studies that point TLR activation as a negative factor in the course of infections, with more cytokine induces inflammation, more damages, and loss of survival rate.

Sickness behaviour is also related to TLR activation, and many neurodegenerative diseases as well.

TLR3 contributes to degeneration of dopamine neurons in an MPTP mouse model of Parkinson’s disease | The Journal of Immunology (jimmunol.org)