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 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 72 h 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-alpha, interleukin-12, and IFN-gamma 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-alpha 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.
Hammerbeck
David M
DM
Department of Pharmacology, 3M Pharmaceuticals, 3M Center, Building 270-3A-10, St. Paul, MN 55144, USA.
Burleson
Gary R
GR
Schuller
Craig J
CJ
Vasilakos
John P
JP
Tomai
Mark
M
Egging
Elaine
E
Cochran
Felicia R
FR
Woulfe
Susan
S
Miller
Richard L
RL
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D053122:Influenza A Virus, H3N2 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D007370:Interferon Type I / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000821:virology; D051381:Rats; D011916:Rats, Inbred F344; D051199:Toll-Like Receptor 7 / Q000008:administration & dosage / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000008:administration & dosage / Q000819:agonists*; D014779:Virus Replication / Q000187:drug effects
D016207:Cytokines; D007370:Interferon Type I; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8