Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats
Toll-like receptors (TLR) detect conserved molecular patterns expressed by pathogens. Detection of the “molecular signature” for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cyt...
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creator | Hammerbeck, David M. Burleson, Gary R. Schuller, Craig J. Vasilakos, John P. Tomai, Mark Egging, Elaine Cochran, Felicia R. Woulfe, Susan Miller, Richard L. |
description | Toll-like receptors (TLR) detect conserved molecular patterns expressed by pathogens. Detection of the “molecular signature” for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-α, interleukin-12, and IFN-γ from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-α administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation. |
doi_str_mv | 10.1016/j.antiviral.2006.07.011 |
format | Article |
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Detection of the “molecular signature” for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-α, interleukin-12, and IFN-γ from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-α administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation.</description><identifier>ISSN: 0166-3542</identifier><identifier>EISSN: 1872-9096</identifier><identifier>DOI: 10.1016/j.antiviral.2006.07.011</identifier><identifier>PMID: 16959331</identifier><identifier>CODEN: ARSRDR</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Animals ; Antibiotics. Antiinfectious agents. 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Detection of the “molecular signature” for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-α, interleukin-12, and IFN-γ from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-α administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation.</description><subject>Animals</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Biological and medical sciences</subject><subject>Cytokine</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Immunity, Innate</subject><subject>Infectious diseases</subject><subject>Influenza</subject><subject>Influenza A Virus, H3N2 Subtype - pathogenicity</subject><subject>Influenza, Human - drug therapy</subject><subject>Influenza, Human - immunology</subject><subject>Influenza, Human - virology</subject><subject>Innate immunity</subject><subject>Interferon</subject><subject>Interferon Type I - metabolism</subject><subject>Leukocytes, Mononuclear - immunology</subject><subject>Lung - virology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Toll-like receptor</subject><subject>Toll-Like Receptor 7 - administration & dosage</subject><subject>Toll-Like Receptor 7 - agonists</subject><subject>Toll-Like Receptor 8 - administration & dosage</subject><subject>Toll-Like Receptor 8 - agonists</subject><subject>Viral diseases</subject><subject>Viral diseases of the respiratory system and ent viral diseases</subject><subject>Virus Replication - drug effects</subject><issn>0166-3542</issn><issn>1872-9096</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1DAQgC1ERZfCXwBf4JbUdhI_jquqFKRKXOBsTZwJ8uJ1trZTCX49Xu2qvSD1NKPxNw_5I-QjZy1nXF7vWojFP_oEoRWMyZaplnH-imy4VqIxzMjXZFNJ2XRDLy7J25x3rILK6DfkkkszmK7jG_KwnfY--lwSFL9EuswU6LRCoGUJoQn-N9KEDg9lSVRRiNP_HjSFX8txCj2kpaAruRbAx1rwcQ4rxr9QM1qX5HfkYoaQ8f05XpGfX25_3Hxt7r_ffbvZ3jeu71hpuB6w15x32o2G8X7UahoHrgH70cHg9AASGWg38G4aFHKmYJC9mUcwUkyquyKfT3PrSQ8r5mL3PjsMASIua7ZSGyGFkS-Cggl95CqoTqBLS84JZ3tIfg_pj-XMHrXYnX3SYo9aLFO2aqmdH84r1nGP03Pf2UMFPp0ByA7CnCA6n5853SsulK7c9sRh_blHj8lm5zE6nHyVUey0-BeP-QfCCbCh</recordid><startdate>200701</startdate><enddate>200701</enddate><creator>Hammerbeck, David M.</creator><creator>Burleson, Gary R.</creator><creator>Schuller, Craig J.</creator><creator>Vasilakos, John P.</creator><creator>Tomai, Mark</creator><creator>Egging, Elaine</creator><creator>Cochran, Felicia R.</creator><creator>Woulfe, Susan</creator><creator>Miller, Richard L.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>200701</creationdate><title>Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats</title><author>Hammerbeck, David M. ; Burleson, Gary R. ; Schuller, Craig J. ; Vasilakos, John P. ; Tomai, Mark ; Egging, Elaine ; Cochran, Felicia R. ; Woulfe, Susan ; Miller, Richard L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-185e481138cb9014b87db518ae4bca5c85a6e0a8c513d57e107a5649fba962d73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Biological and medical sciences</topic><topic>Cytokine</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Immunity, Innate</topic><topic>Infectious diseases</topic><topic>Influenza</topic><topic>Influenza A Virus, H3N2 Subtype - pathogenicity</topic><topic>Influenza, Human - drug therapy</topic><topic>Influenza, Human - immunology</topic><topic>Influenza, Human - virology</topic><topic>Innate immunity</topic><topic>Interferon</topic><topic>Interferon Type I - metabolism</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Lung - virology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Toll-like receptor</topic><topic>Toll-Like Receptor 7 - administration & dosage</topic><topic>Toll-Like Receptor 7 - agonists</topic><topic>Toll-Like Receptor 8 - administration & dosage</topic><topic>Toll-Like Receptor 8 - agonists</topic><topic>Viral diseases</topic><topic>Viral diseases of the respiratory system and ent viral diseases</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hammerbeck, David M.</creatorcontrib><creatorcontrib>Burleson, Gary R.</creatorcontrib><creatorcontrib>Schuller, Craig J.</creatorcontrib><creatorcontrib>Vasilakos, John P.</creatorcontrib><creatorcontrib>Tomai, Mark</creatorcontrib><creatorcontrib>Egging, Elaine</creatorcontrib><creatorcontrib>Cochran, Felicia R.</creatorcontrib><creatorcontrib>Woulfe, Susan</creatorcontrib><creatorcontrib>Miller, Richard L.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Antiviral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hammerbeck, David M.</au><au>Burleson, Gary R.</au><au>Schuller, Craig J.</au><au>Vasilakos, John P.</au><au>Tomai, Mark</au><au>Egging, Elaine</au><au>Cochran, Felicia R.</au><au>Woulfe, Susan</au><au>Miller, Richard L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats</atitle><jtitle>Antiviral research</jtitle><addtitle>Antiviral Res</addtitle><date>2007-01</date><risdate>2007</risdate><volume>73</volume><issue>1</issue><spage>1</spage><epage>11</epage><pages>1-11</pages><issn>0166-3542</issn><eissn>1872-9096</eissn><coden>ARSRDR</coden><abstract>Toll-like receptors (TLR) detect conserved molecular patterns expressed by pathogens. Detection of the “molecular signature” for RNA viruses including influenza has been attributed to TLR3, TLR7, and TLR8. In the present study, compound 3M-011 was shown to be a synthetic human TLR7/8 agonist and cytokine inducer. 3M-011 was investigated as a stand-alone immune response modifier in a rat model of human influenza. Intranasal (IN) administration of 3M-011 significantly inhibited H3N2 influenza viral replication in the nasal cavity when administered from 72h before IN viral inoculation to 6h after inoculation. Viral inhibition correlated with the ability of the TLR7/8 agonist to stimulate type I interferon (IFN) and other cytokines such as tumor necrosis factor-α, interleukin-12, and IFN-γ from rat peripheral blood mononuclear cells. Prophylactic administration of TLR7/8 agonist also suppressed influenza viral titers in the lung, which corresponded with local IFN production. The activity of the TLR7/8 agonist resulted in greater inhibition of viral titers compared to rat recombinant IFN-α administered in a comparable dosing regimen. These studies indicate that TLR7/8 agonists may have prophylactic and therapeutic benefits in the treatment of respiratory viral infections, such as influenza, when administered prior to or shortly after viral inoculation.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>16959331</pmid><doi>10.1016/j.antiviral.2006.07.011</doi><tpages>11</tpages></addata></record> |
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subjects | Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Cytokine Cytokines - metabolism Disease Models, Animal Female Human viral diseases Humans Immunity, Innate Infectious diseases Influenza Influenza A Virus, H3N2 Subtype - pathogenicity Influenza, Human - drug therapy Influenza, Human - immunology Influenza, Human - virology Innate immunity Interferon Interferon Type I - metabolism Leukocytes, Mononuclear - immunology Lung - virology Medical sciences Pharmacology. Drug treatments Rats Rats, Inbred F344 Toll-like receptor Toll-Like Receptor 7 - administration & dosage Toll-Like Receptor 7 - agonists Toll-Like Receptor 8 - administration & dosage Toll-Like Receptor 8 - agonists Viral diseases Viral diseases of the respiratory system and ent viral diseases Virus Replication - drug effects |
title | Administration of a dual toll-like receptor 7 and toll-like receptor 8 agonist protects against influenza in rats |
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