Ligation of Dectin-1 by fungal glucans elicits a Th17 response that is necessary for clearing many fungal pathogens. Laminarin is a (1→3, 1→6)-β-glucan that is widely reported to be a Dectin-1 antagonist, however, there are reports that laminarin is also a Dectin-1 agonist. To address this controversy, we assessed the physical properties, structure, purity, Dectin-1 binding, and biological activity of five different laminarin preparations from three different commercial sources. The proton nuclear magnetic resonance analysis indicated that all of the preparations contained laminarin although their molecular mass varied considerably (4400-34,400 Da). Two of the laminarins contained substantial quantities of very low m.w. compounds, some of which were not laminarin. These low m.w. moieties could be significantly reduced by extensive dialysis. All of the laminarin preparations were bound by recombinant human Dectin-1 and mouse Dectin-1, but the affinity varied considerably, and binding affinity did not correlate with Dectin-1 agonism, antagonism, or potency. In both human and mouse cells, two laminarins were Dectin-1 antagonists and two were Dectin-1 agonists. The remaining laminarin was a Dectin-1 antagonist, but when the low m.w. moieties were removed, it became an agonist. We were able to identify a laminarin that is a Dectin-1 agonist and a laminarin that is Dectin-1 antagonist, both of which are relatively pure preparations. These laminarins may be useful in elucidating the structure and activity relationships of glucan/Dectin-1 interactions. Our data demonstrate that laminarin can be either a Dectin-1 antagonist or agonist, depending on the physicochemical properties, purity, and structure of the laminarin preparation employed.
Mycobacterium tuberculosis (Mtb) continues to be a major health threat worldwide,
and
the development of Mtb vaccines could play a pivotal
role in the prevention and control of this devastating epidemic. Th17-mediated
immunity has been implicated in disease protection correlates of immune
protection against Mtb. Currently, there are no approved
adjuvants capable of driving a Th17 response in a vaccine setting.
Recent clinical trial results using trehalose dibehenate have demonstrated
a formulation-dependant proof of concept adjuvant system CAF01 capable
of inducing long-lived protection. We have discovered a new class
of Th17-inducing vaccine adjuvants based on the natural product Brartemicin.
We synthesized and evaluated the capacity of a library of aryl trehalose
derivatives to drive immunostimulatory reresponses and evaluated the
structure–activity relationships in terms of the ability to
engage the Mincle receptor and induce production of innate cytokines
from human and murine cells. We elaborated on the structure–activity
relationship of the new scaffold and demonstrated the ability of the
lead entity to induce a pro-Th17 cytokine profile from primary human
peripheral blood mononuclear cells and demonstrated efficacy in generating
antibodies in combination with tuberculosis antigen M72 in a mouse
model.
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