Synergistic TLR2/6 and TLR9 activation protects mice against lethal influenza pneumonia.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Antiviral Agents/*administration & dosage ; Orthomyxoviridae Infections/*drug therapy ; Pneumonia, Viral/*prevention & control ; Toll-Like Receptor 2/*agonists ; Toll-Like Receptor 6/*agonists ; Toll-Like Receptor 9/*agonists; Animals ; Antiviral Agents/pharmacology ; Drug Combinations ; Drug Synergism ; Influenza A Virus, H1N1 Subtype/drug effects ; Influenza A Virus, H1N1 Subtype/physiology ; Influenza A virus/drug effects ; Influenza A virus/physiology ; Mice ; Orthomyxoviridae Infections/complications ; Orthomyxoviridae Infections/mortality ; Pneumonia, Viral/etiology ; Pneumonia, Viral/mortality ; Survival Analysis ; Toll-Like Receptor 2/metabolism ; Toll-Like Receptor 6/metabolism ; Toll-Like Receptor 9/metabolism ; Viremia/drug therapy

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.

N Engl J Med. 2008 Feb 14;358(7):716-27. (PMID: 18272895)
Am J Respir Crit Care Med. 2008 Jun 15;177(12):1322-30. (PMID: 18388354)
Influenza Other Respir Viruses. 2011 Mar;5(2):67-75. (PMID: 21306569)
Am J Epidemiol. 2006 Jan 15;163(2):181-7. (PMID: 16319291)
Cell Microbiol. 2007 Jul;9(7):1641-6. (PMID: 17506818)
J Virol. 2005 Mar;79(5):2910-9. (PMID: 15709010)
Infect Immun. 1977 Jan;15(1):221-9. (PMID: 832899)
PLoS One. 2009;4(1):e4176. (PMID: 19137067)
MMWR Morb Mortal Wkly Rep. 2011 Aug 19;60(32):1078-82. (PMID: 21849964)
MMWR Morb Mortal Wkly Rep. 2011 Jun 17;60(23):781-5. (PMID: 21681175)
Vaccine. 2009 Feb 25;27(9):1354-64. (PMID: 19150474)
Cell Tissue Res. 2011 Jan;343(1):13-21. (PMID: 20848130)
Respir Res. 2009 Jul 27;10:70. (PMID: 19635139)
Vaccine. 2010 Sep 7;28 Suppl 4:D45-53. (PMID: 20713260)
ChemMedChem. 2006 Sep;1(9):1007-14. (PMID: 16952134)
Virology. 2010 Oct 10;406(1):80-7. (PMID: 20667572)
Annu Rev Physiol. 2010;72:413-35. (PMID: 20148683)
Nat Rev Drug Discov. 2006 Jun;5(6):471-84. (PMID: 16763660)
Am J Respir Cell Mol Biol. 2004 Oct;31(4):382-94. (PMID: 15191915)
Vaccine. 2011 Apr 27;29(19):3548-57. (PMID: 21419775)
Vaccine. 2011 Jul 1;29 Suppl 1:A2-7. (PMID: 21684422)
Semin Respir Crit Care Med. 2011 Aug;32(4):373-92. (PMID: 21858743)
Semin Respir Crit Care Med. 2011 Aug;32(4):409-22. (PMID: 21858746)
JAMA. 2011 Jul 13;306(2):200-1. (PMID: 21750298)
Antiviral Res. 1992 Jan;17(1):33-42. (PMID: 1736809)
Vaccine. 2002 Aug 19;20(25-26):3055-67. (PMID: 12163257)
Adv Drug Deliv Rev. 2009 Mar 28;61(3):195-204. (PMID: 19211030)
Am J Respir Cell Mol Biol. 2010 Jan;42(1):40-50. (PMID: 19329554)
Haematologica. 2011 Jun;96(6):896-904. (PMID: 21422117)
Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11029-33. (PMID: 8248207)
N Engl J Med. 2008 Jan 17;358(3):261-73. (PMID: 18199865)
Expert Rev Vaccines. 2011 Feb;10(2):175-86. (PMID: 21332267)
Emerg Infect Dis. 2006 Jan;12(1):44-7. (PMID: 16494716)
Vaccine. 2009 May 26;27(25-26):3481-3. (PMID: 19200852)
J Endotoxin Res. 2004;10(6):431-8. (PMID: 15588427)
Eur J Immunol. 2004 Jan;34(1):251-62. (PMID: 14971051)
MMWR Morb Mortal Wkly Rep. 2011 Aug 19;60(32):1073-7. (PMID: 21849963)
J Immunol. 2011 May 15;186(10):5916-26. (PMID: 21482737)
Br J Pharmacol. 2011 May;163(1):195-206. (PMID: 21250981)
J Infect Dis. 2011 Jan 1;203(1):25-31. (PMID: 21148493)
Am J Med. 2011 Sep;124(9):e9; author reply e11. (PMID: 21854886)
PLoS Med. 2006 Feb;3(2):e76. (PMID: 16401173)
APMIS. 2011 Sep;119(9):565-573. (PMID: 21851413)
Am J Med. 2008 Apr;121(4):258-64. (PMID: 18374680)
J Med Virol. 2006 Jul;78(7):954-63. (PMID: 16721854)
Bull Hist Med. 2002 Spring;76(1):105-15. (PMID: 11875246)
PLoS One. 2008 May 28;3(5):e2268. (PMID: 18509468)

P30 CA016672 United States CA NCI NIH HHS; U01 AI082226 United States AI NIAID NIH HHS; U01 AI82226 United States AI NIAID NIH HHS

GEO GSE26864; GSE28994

0 (Antiviral Agents)
0 (Drug Combinations)
0 (Tlr2 protein, mouse)
0 (Tlr6 protein, mouse)
0 (Tlr9 protein, mouse)
0 (Toll-Like Receptor 2)
0 (Toll-Like Receptor 6)
0 (Toll-Like Receptor 9)

Date Created: 20120203 Date Completed: 20120705 Latest Revision: 20240317

20240317

PMC3267724

10.1371/journal.pone.0030596

22299046