Toll-like receptor 3 agonist protection against experimental Francisella tularensis respiratory tract infection.
We investigated whether Toll-like receptor 3 (TLR3) stimulation would protect the host from inhaled Francisella tularensis. TLR3 is expressed by respiratory epithelial cells and macrophages and can be activated by a synthetic double-stranded RNA ligand called polyinosine-polycytosine [poly(I:C)]. Thus, we evaluated poly(I:C) as a novel treatment against inhaled F. tularensis. In vivo, BALB/c mice intranasally (i.n.) treated with poly(I:C) (100 microg/mouse) 1 h before or after Schu 4 or LVS (100 CFU) i.n. challenge showed that poly(I:C) treatment significantly reduced bacterial load in the lungs (P < 0.05). Bronchoalveolar lavage from poly(I:C)-treated mice alone or combined with F. tularensis infection significantly increased cytokine secretion and enhanced neutrophil influx to lung tissues. Poly(I:C) responses were transient but significantly prolonged the survival of treated mice after i.n. F. tularensis challenge relative to mock treated animals. This prolonged survival providing a longer window for initiation of levofloxacin (LEVO) treatment (40 mg/kg). Animals treated with poly(I:C), challenged with F. tularensis, and then treated with LEVO 5 days later had 100% survival relative to 0% survival in animals receiving LEVO alone. Mechanistically, poly(I:C) given to human monocyte-derived macrophages before or after Schu 4 or LVS challenge (multiplicity of infection, 20:1) had significantly reduced intracellular bacterial replication (P < 0.05). These data suggest that poly(I:C) may represent a potential therapeutic agent against inhaled F. tularensis that prolongs survival and the opportunity to initiate standard antibiotic therapy (i.e., LEVO).
Pyles
Richard B
RB
Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas 77555-0436, USA.
Jezek
G Eric
GE
Eaves-Pyles
Tonyia D
TD
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000382:microbiology; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D016207:Cytokines / Q000032:analysis; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D064704:Levofloxacin; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000382:microbiology; D009504:Neutrophils / Q000276:immunology; D015242:Ofloxacin / Q000627:therapeutic use; D011070:Poly I-C / Q000494:pharmacology*; D012141:Respiratory Tract Infections / Q000276:immunology*; D016019:Survival Analysis; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000276:immunology*; D014406:Tularemia / Q000276:immunology / Q000517:prevention & control*
D000900:Anti-Bacterial Agents; D016207:Cytokines; D007155:Immunologic Factors; D051196:Toll-Like Receptor 3; D064704:Levofloxacin; D015242:Ofloxacin; D011070:Poly I-C