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.

Intranasal Prophylaxis with CpG Oligodeoxynucleotide Can Protect against Yersinia pestis Infection

“…Previous studies established that modifying the LPS structure of Y. pestis or treating mice with lipid A mimetics can stimulate TLR4-dependent innate defense against plague (18,21,22). Our studies extend these observations to treatment with CpG ODN, a mimetic of bacterial DNA that stimulates immunity via TLR9.…”

“…Indeed, treating mice with mimetics of the inflammatory forms of LPS lipid A protect against pulmonary Y. pestis challenge in a TLR4-dependent manner (22). Bacterial DNA can also be immunostimulatory due to the presence of unmethylated cytosine-phosphate-guanidine (CpG) repeats, which stimulate TLR9-dependent cytokine production and lymphocyte activation (23,24).…”

IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

“…Y. pestis, the causative agent of plague, alters the degree of LPS acylation according to host temperature, producing hexaacylated lipid A at temperatures between 21 and 27°C (flea temperature) and tetraacylated lipid A at 37°C (host temperature) (8). Genetically modified Y. pestis harboring fully potent LPS is completely avirulent, suggesting that the evasion of LPS-TLR4-mediated inflammation is critical for Y. pestis virulence (52,53). Very recently, two reports have highlighted in S. flexneri serotype two adaptation mechanisms involving LPS modifications and amount, respectively (54,55).…”

Lipid A mimetics are potent adjuvants for an intranasal pneumonic plague vaccine

“…The AGPs employed in this study (CRX-524 and CRX-527) have acyl side chains of 10 carbons and contain either H or a carboxyl group respectively at the aglycon unit [31]. We have shown these compounds, when administered intranasally, induce high levels of TNF-α, IL-12p70, and IFN-γ in murine lung tissue [32]. Using a murine model of pneumonic plague, we tested an intranasal vaccine using AGPs as adjuvant with F1 and/or V-antigen to determine i) the best concentrations of AGPs; ii) the effect of primary and secondary vaccine regimens; iii) the shortest duration to protection; iv) the requirement for TLR4 stimulation; and v) protection in rats.…”