Induction of innate immunity by lipid A mimetics increases survival from pneumonic plague.
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.
Airhart
Christina L
CL
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Rohde
Harold N
HN
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Bohach
Gregory A
GA
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Hovde
Carolyn J
CJ
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Deobald
Claudia F
CF
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
Lee
Stephen S
SS
Department of Statistics, University of Idaho, Moscow, ID 83844-3052, USA.
Minnich
Scott A
SA
Department of Microbiology, Molecular Biology, and Biochemistry, University of Idaho, Moscow, ID 83844-3052, USA.
D000818:Animals; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005944:Glucosamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008050:Lipid A / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000276:immunology; D010930:Plague / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology / Q000401:mortality*; D013047:Specific Pathogen-Free Organisms / Q000276:immunology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000276:immunology; D015010:Yersinia pestis / Q000472:pathogenicity / Q000502:physiology*
C530111:AGP 524; C530112:AGP 527; D016207:Cytokines; D008050:Lipid A; D009943:Organophosphorus Compounds; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005944:Glucosamine