Is There a Role for Immunoregulatory and Antiviral Oligonucleotides Acting in the Extracellular Space? A Review and Hypothesis

Abstract

Here, we link approved and emerging nucleic acid-based therapies with the expanding universe of small non-coding RNAs (sncRNAs) and the innate immune responses that sense oligonucleotides taken up into endosomes. The Toll-like receptors (TLRs) 3, 7, 8, and 9 are located in endosomes and can detect nucleic acids taken up through endocytic routes. These receptors are key triggers in the defense against viruses and/or bacterial infections, yet they also constitute an Achilles heel towards the discrimination between self- and pathogenic nucleic acids. The compartmentalization of nucleic acids and the activity of nucleases are key components in avoiding autoimmune reactions against nucleic acids, but we still lack knowledge on the plethora of nucleic acids that might be released into the extracellular space upon infections, inflammation, and other stress responses involving increased cell death. We review recent findings that a set of single-stranded oligonucleotides (length of 25–40 nucleotides (nt)) can temporarily block ligands destined for endosomes expressing TLRs in human monocyte-derived dendritic cells. We discuss knowledge gaps and highlight the existence of a pool of RNA with an approximate length of 30–40 nt that may still have unappreciated regulatory functions in physiology and in the defense against viruses as gatekeepers of endosomal uptake through certain routes.

The Role of Toll-like Receptors (TLRs) and Their Related Signaling Pathways in Viral Infection and Inflammation

“…Overall, this Special Issue illustrates the two sides of TLRs as drivers of pathogenesis of acute bacterial and viral infections, including COVID-19, but also as potent players for antiviral, antibacterial, and anti-cancer immune activation. Dependent on the direction of the disbalance in TLR activation in different pathologies, TLR agonists [ 9 , 10 ] or antagonists [ 2 , 4 , 6 ] may be of interest. For stimulating innate immune responses against bacterial, viral, or parasitic invasions or for use as an adjuvant in anti-cancer vaccination, one single selected TLR agonist may be sufficient to trigger an effective innate immune response.…”

“…The reviews focus on the topics of viral infection-induced inflammation, such as SARS-CoV-2 [ 1 , 2 ] and hepatitis C virus (HCV) infection [ 3 ], related to TLR-induced pathological processes; they also discuss the protective role of TLRs against viral infection and the strategies used by viruses to inhibit TLR activation. Furthermore, the role of immunoregulatory and antiviral oligonucleotides is addressed [ 4 ]. The six experimental research papers cover topics ranging from TLR2 and TLR4 polymorphisms and susceptibility to bacterial sepsis [ 5 ]; decrease in endotoxin-induced activation of TLR4 signaling by xanthohumol-rich hop extract [ 6 ], advanced glycosylation end-products and TLR- induced changes in aquaporin-3 expression in mouse keratinocytes [ 7 ]; TLR4 signaling in periodontal ligament cells in response to mechanical compression [ 8 ]; identification of optimal TLR8 ligand by altering the position of 2′-O-ribose methylation [ 9 ]; to a breast cancer vaccine containing a novel TLR7 agonist showing antitumor effects [ 10 ].…”

“…Some single-stranded oligonucleotides (ssONs) may have the capacity to inhibit endocytic pathways and have immunoregulatory functions. In addition, this pool of 30–40 oligonucleotide RNAs may also prevent the entry of certain viruses ( Figure 4 ) [ 4 ].…”