Induction of innate immunity by lipid A mimetics increases survival from pneumonic plague.

Abstract

This study analysed the effect of priming the innate immune system using synthetic lipid A mimetics in a Yersinia pestis murine pulmonary infection model. Two aminoalkyl glucosaminide 4-phosphate (AGP) Toll-like receptor 4 (TLR4) ligands, delivered intranasally, extended time to death or protected against a lethal Y. pestis CO92 challenge. The level of protection was dependent upon the challenge dose of Y. pestis and the timing of AGP therapy. Protection correlated with cytokine induction and a decreased bacterial burden in lung tissue. AGP protection was TLR4-dependent and was not evidenced in transgenic TLR4-deficient mice. AGP therapy augmented with subtherapeutic doses of gentamicin produced dramatically enhanced survival. Combined, these results indicated that AGPs may be useful in protection of immunologically naive individuals against plague and potentially other infectious agents, and that AGP therapy may be used synergistically with other therapies.

• Authors: Christina L Airhart, Harold N Rohde, Gregory A Bohach, Carolyn J Hovde, Claudia F Deobald, Stephen S Lee, Scott A Minnich
• Journal: Microbiology (Reading, England) (Microbiology (Reading)) Vol. 154 Issue Pt 7 Pg. 2131-2138 (Jul 2008) ISSN: 1350-0872 [Print] England
• PMID: 18599840 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGP 524
• AGP 527
• Cytokines
• Lipid A
• Organophosphorus Compounds
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Glucosamine

Topics

• Animals
• Cytokines (immunology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Glucosamine (administration & dosage, analogs & derivatives, immunology)
• Humans
• Immunity, Innate
• Lipid A (immunology)
• Lung (immunology, microbiology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Organophosphorus Compounds (administration & dosage, immunology)
• Plague (drug therapy, immunology, microbiology, mortality)
• Specific Pathogen-Free Organisms (immunology)
• Time Factors
• Toll-Like Receptor 4 (immunology)
• Yersinia pestis (pathogenicity, physiology)