Toll-like receptor 3 agonist protection against experimental Francisella tularensis respiratory tract infection

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

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 monocytederived 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).

Original languageEnglish (US)
Pages (from-to)1700-1710
Number of pages11
JournalInfection and Immunity
Volume78
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

Toll-Like Receptor 3
Francisella tularensis
Levofloxacin
Respiratory Tract Infections
Survival
Macrophages
Tularemia
Therapeutics
Lung
Double-Stranded RNA
Bacterial Load
Bronchoalveolar Lavage
Neutrophils
Epithelial Cells
Cytokines
Anti-Bacterial Agents
Ligands
Infection

ASJC Scopus subject areas

  • Immunology
  • Microbiology
  • Parasitology
  • Infectious Diseases

Cite this

Toll-like receptor 3 agonist protection against experimental Francisella tularensis respiratory tract infection. / Pyles, Richard; Jezek, G. Eric; Eaves-Pyles, Tonyia.

In: Infection and Immunity, Vol. 78, No. 4, 04.2010, p. 1700-1710.

Research output: Contribution to journalArticle

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