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

• Published in: Vaccine Vol. 27; no. 25; pp. 3481 - 3483
• Main Authors: Wong, J.P, Christopher, M.E, Viswanathan, S, Karpoff, N, Dai, X, Das, D, Sun, L.Q, Wang, M, Salazar, A.M
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Kidlington Elsevier Ltd 26-05-2009; Elsevier; Elsevier Limited; Published by Elsevier Ltd
• Subjects: Agonists; Allergy and Immunology; Animal tissues; Animals; Antiviral activity; Antiviral Agents - pharmacology; Applied microbiology; Avian flu; Biological and medical sciences; Carboxymethylcellulose Sodium - administration & dosage; Carboxymethylcellulose Sodium - analogs & derivatives; Carboxymethylcellulose Sodium - pharmacology; Crystal structure; Drug dosages; Drug resistance; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Immune system; Infections; Influenza A virus; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H3N2 Subtype - drug effects; Influenza A Virus, H5N1 Subtype - drug effects; Influenza virus; Kinases; Liposomes; Lungs; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Nucleic acids; Oligodeoxyribonucleotides - pharmacology; Orthomyxoviridae Infections - prevention & control; Poly I-C - administration & dosage; Poly I-C - pharmacology; Polylysine - administration & dosage; Polylysine - analogs & derivatives; Polylysine - pharmacology; Protection; Proteins; RNA, Messenger - analysis; Signal Transduction - drug effects; Signaling pathway; Substance abuse treatment; Toll-like receptor; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - physiology; Vaccines, antisera, therapeutical immunoglobulins and monoclonal antibodies (general aspects); Virology; Viruses; Agonists; Liposomes; Signaling pathway; Influenza virus; Protection; Toll-like receptor; Liposome; Orthomyxoviridae; Toll like receptor; Influenzavirus; Infection; Virus; Viral disease
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2009.01.048

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.