Toll-Like Receptor 3 Agonist Protection against Experimental Francisella tularensis Respiratory Tract Infection

• Published in: Infection and Immunity 2010-04, Vol.78 (4), p.1700-1710
• Main Authors: Pyles, Richard B, Jezek, G. Eric, Eaves-Pyles, Tonyia D
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - therapeutic use; Bacteriology; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Bronchoalveolar Lavage Fluid - microbiology; Cells, Cultured; Colony Count, Microbial; Cytokines - analysis; Female; Francisella tularensis - immunology; Fundamental and applied biological sciences. Psychology; Host Response and Inflammation; Humans; Immunologic Factors - pharmacology; Levofloxacin; Lung - microbiology; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Monocytes - immunology; Monocytes - microbiology; Neutrophils - immunology; Ofloxacin - therapeutic use; Poly I-C - pharmacology; Respiratory Tract Infections - immunology; Survival Analysis; Toll-Like Receptor 3 - agonists; Toll-Like Receptor 3 - immunology; Tularemia - immunology; Tularemia - prevention & control
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00736-09

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 μg/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).