Synergistic TLR2/6 and TLR9 activation protects mice against lethal influenza pneumonia.
Lower respiratory tract infections caused by influenza A continue to exact unacceptable worldwide mortality, and recent epidemics have emphasized the importance of preventative and containment strategies. We have previously reported that induction of the lungs' intrinsic defenses by aerosolized treatments can protect mice against otherwise lethal challenges with influenza A virus. More recently, we identified a combination of Toll like receptor (TLR) agonists that can be aerosolized to protect mice against bacterial pneumonia. Here, we tested whether this combination of synthetic TLR agonists could enhance the survival of mice infected with influenza A/HK/8/68 (H3N2) or A/California/04/2009 (H1N1) influenza A viruses. We report that the TLR treatment enhanced survival whether given before or after the infectious challenge, and that protection tended to correlate with reductions in viral titer 4 d after infection. Surprisingly, protection was not associated with induction of interferon gene expression. Together, these studies suggest that synergistic TLR interactions can protect against influenza virus infections by mechanisms that may provide the basis for novel therapeutics.
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Michael J
MJ
Tuvim
Brian E
BE
Gilbert
Burton F
BF
Dickey
Scott E
SE
Evans
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011024:Pneumonia, Viral / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*; D016019:Survival Analysis; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000819:agonists* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000378:metabolism; D014766:Viremia / Q000188:drug therapy
D000998:Antiviral Agents; D004338:Drug Combinations; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D051217:Toll-Like Receptor 9