Abstract
Accumulating evidence suggests important functions for human Toll-like receptor 8 in vivo in tuberculosis and autoimmune diseases. However, these studies are limited by the lack of specific agonists and by the fact that the homology of TLR8 in human and mice is not sufficient to rely on mouse models. In this study, we examined the role of human TLR8 in the disease progression of experimental Mycobacterium tuberculosis (Mtb) infection, as well as the benefits provided by a TLR8 agonist against Mtb challenge in a human TLR8 transgenic mouse. We found that the expression of human TLR8 in C57BL/6 mice permits higher bacilli load in tissues. A vaccine formulated with ESAT-6, aluminum hydroxide, and TLR8 agonist provided protection against Mtb challenge, with a high percentage of CD44hiCD62Lhi TCM. Using ovalbumin as a model antigen, we demonstrated that the activation of TLR8 enhanced the innate and adaptive immune response, and provided a sustained TCM formation and Th1 type humoral response, which were mainly mediated by type I IFN signaling. Further research is required to optimize the vaccine formulation and seek optimal combinations of different TLR agonists, such as TLR4, for better adjuvanticity in this animal model.
Highlights
As a continued threat to global health, TB epidemics have caused 1.4 million deaths per year
Using humanized TLR8 mice, Dowling and colleagues reported that TLR8 agonist polymersomes induced high IL-12p70 levels and newborn DC maturation profiles similar to those induced by Bacillus Calmette–Guérin (BCG) [26]
Several reports indicate an association between TLR8 and TB; the role of TLR8 in the process and pathogenesis of TB is still not well understood
Summary
As a continued threat to global health, TB epidemics have caused 1.4 million deaths per year. The spread of multidrug-resistant TB increases the difficulty for prevention and treatment. A new TB vaccine is potentially the most powerful tool to end TB, and seeking new adjuvants is one important direction toward its development. Many toll-like receptor ligands have been synthesized and discovered, and many of them have been confirmed as promising adjuvant candidates. Agonists of TLR2 [1], TLR4 [2, 3] (GLA-SE, AS01), and TLR9 (IC31) [4] have all demonstrated the ability to increase the protective effect of the Mtb vaccine.
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