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      Development of mucosal adjuvants for intranasal vaccine for H5N1 influenza viruses

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          Abstract

          An increasing number of infections of highly pathogenic avian influenza virus (H5N1) in humans has been reported in South-East Asia and other areas of the world. High mortality (>60%) of this viral infection and its pathosis of systemic infection are features of this new human disease. Moreover, there is great concern that this avian H5N1 virus could cause a pandemic of new influenza in humans, once it acquires the ability for human to human transmission. To prevent such highly contagious infectious diseases as influenza, it is essential to prepare effective vaccines. Especially in the case of new influenza virus, we cannot predict the strain which will cause the pandemic. In such a situation, a vaccine that induces cross-protective immunity against variant viruses is extremely important. However currently used parenteral seasonal influenza vaccine is strain-specific, and is less effective against variant viruses. In order to overcome the weakness of current vaccines we need to learn from the immune responses induced by natural infection with influenza viruses. In the case of mucosally acquired acute respiratory infection such as influenza, mucosal immunity induced by natural infection plays important role in protection against the infection, as mucosal secretory IgA antibody plays an important role in cross-protection. In this review we describe the advantages and development of mucosal vaccine against highly pathogenic H5N1 influenza viruses.

          Most cited references55

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            Recognition of single-stranded RNA viruses by Toll-like receptor 7.

            Viral infection of mammalian host results in the activation of innate immune responses. Toll-like receptors (TLRs) have been shown to mediate the recognition of many types of pathogens, including viruses. The genomes of viruses possess unique characteristics that are not found in mammalian genomes, such as high CpG content and double-stranded RNA. These genomic nucleic acids serve as molecular signatures associated with viral infections. Here we show that TLR7 recognizes the single-stranded RNA viruses, vesicular stomatitis virus and influenza virus. The recognition of these viruses by plasmacytoid dendritic cells and B cells through TLR7 results in their activation of costimulatory molecules and production of cytokines. Moreover, this recognition required intact endocytic pathways. Mice deficient in either the TLR7 or the TLR adaptor protein MyD88 demonstrated reduced responses to in vivo infection with vesicular stomatitis virus. These results demonstrate microbial ligand recognition by TLR7 and provide insights into the pathways used by the innate immune cells in the recognition of viral pathogens.
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              Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.

              Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-kappaB and the production of type I interferons (IFNs). TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-kappaB and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2009
                2009
                26 March 2009
                : 5
                : 125-132
                Affiliations
                Laboratory of Infectious Disease Pathology, Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
                Author notes
                Correspondence: Hideki Hasegawa, Department of Pathology, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan, Tel +81-42-561-0771, Fax +81-42-561-6572, Email hasegawa@ 123456nih.go.jp
                Article
                tcrm-5-0125
                10.2147/TCRM.S3297
                2697507
                19436601
                b4b35708-0333-468f-8472-c31eb4d68456
                © 2009 Hasegawa et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                Categories
                Review

                Medicine
                influenza virus,mucosal immunity,secretory iga antibody,adjuvant
                Medicine
                influenza virus, mucosal immunity, secretory iga antibody, adjuvant

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