Activation of toll-like receptor signaling pathway for protection against influenza virus infection

Abstract

This study aims to evaluate the antiviral role of nucleic acid-based agonists for the activation of toll-like receptor (TLR) signaling pathways, and its protective role in respiratory influenza A virus infections. TLR-3 is expressed on myeloid dendritic cells, respiratory epithelium, and macrophages, and appears to play a central role in mediating both the antiviral and inflammatory responses of the innate immunity in combating viral infections. Influenza viruses can effectively inhibit the host's ability to produce interferons, and thereby suppress the immune system's antiviral defence mechanisms. Poly ICLC is a synthetic double stranded RNA comprising of polyriboinosinic-poly ribocytidylic acid (Poly IC) stabilized with l-lysine (L) and carboxymethylcellulose (C). Poly ICLC and liposome-encapsulated Poly ICLC (LE Poly ICLC) are TLR-3 agonists and are potent inducer of interferons and natural killer cells. Intranasal pre-treatment of mice with Poly ICLC and LE Poly ICLC provided high level of protection against lethal challenge with a highly lethal avian H5N1 influenza (HPAI) strain (A/H5N1/chicken/Henan clade 2), and against lethal seasonal influenza A/PR/8/34 [H1N1] and A/Aichi/2 [H3N2] virus strains. The duration of protective antiviral immunity to multiple lethal doses of influenza virus A/PR/8/34 virus had been previously found to persist for up to 3 weeks in mice for LE Poly ICLC and 2 weeks for Poly ICLC. Similarly, pre-treatment of mice with CpG oligonucleotides (TLR-9 agonist) was also found to provide complete protection against influenza A/PR/8/34 infection in mice. RT-PCR analysis of lung tissues of mice treated with Poly ICLC and LE Poly ICLC revealed upregulation of TLR-3 mRNAs gene expression. Taken together, these results do support the potential role of TLR-3 and TLR-9 agonists such as Poly ICLC and LE Poly ICLC in protection against lethal seasonal and HPAI virus infection.

OLYMPUS: An automated hybrid clustering method in time series gene expression. Case study: Host response after Influenza A (H1N1) infection

“…(cluster 17). Similar results were observed with regard to Toll-like receptor pathway (clusters 3, 7 and 17), which appears to play a central role in mediating both the antiviral and inflammatory responses of the innate immunity in combating viral infections [39].…”

Role of human Toll‐like receptors in naturally occurring influenza A infections

“…Ideally, the respiratory epithelial cells should also be studied (especially for TLR3 and RLRs);3, 5, 8, 16 however, obtaining such specimens (e.g., with bronchoalveolar lavage ) is generally infeasible in patients with influenza. Studying circulating cells exposed to the pulmonary bed has been shown to provide close estimates 6, 7, 20, 22, 32, 41.…”

“…In vitro studies have also revealed an additional cytosolic system of retinoic acid‐inducible gene‐1 (RIG‐1)‐like receptor proteins (RLRs) that detect influenza viral RNAs, contributing to the innate responses 3, 7, 10, 13. Recently, data from animal studies have further shown that targeting the TLRs (with agonists) may rapidly upregulate the innate immunity to provide broad‐range, virus strain non‐specific protection against lethal influenza challenge 4, 11, 14, 15, 16, 17. However, our understanding on TLR's importance in natural influenza is very limited because of lack of clinical data.…”

Dendritic Cell Activation by Recombinant Hemagglutinin Proteins of H1N1 and H5N1 Influenza A Viruses

“…Different DC subsets can induce specific TLR pathways following influenza virus infection. For instance, mDCs are activated via TLR3 and TLR9 (41), whereas pDCs are activated via TLR7 (11). The CD8␣ ϩ conventional DC subset specifically initiates CTL immunity in response to influenza virus infection (4).…”