Investigations into novel bacterial drug targets and vaccines are necessary to overcome tuberculosis. Lipomannan (LM), found on the surface of Mycobacterium tuberculosis (Mtb), is actively involved in the pathogenesis and survival of Mtb. Here, we report for the first time a rapid synthesis and biological activities of an LM glycan backbone, α(1-6)mannans. The rapid synthesis is achieved via a regio- and stereoselective ring opening polymerization to generate multiple glycosidic bonds in one simple chemical step, allowing us to finish assembling the defined polysaccharides of 5-20 units within days rather than years. Within the same pot, the polymerization is terminated by a thiol-linker to serve as a conjugation point to carrier proteins and surfaces for immunological experiments. The synthetic glycans are found to have adjuvant activities in vivo. The interactions with DC-SIGN demonstrated the significance of α(1-6)mannan motif present in LM structure. Moreover, surface plasmon resonance (SPR) showed that longer chain of synthetic α(1-6)mannans gain better lectin's binding affinity. The chemically defined components of the bacterial envelope serve as important tools to reveal the interactions of Mtb with mammalian hosts and facilitate the determination of the immunologically active molecular components.
Lipomannan (LM), a glycophospholipid
found on the cell surface
of mycobacteria, involves the virulence and survival in host cells.
However, there is little to no information on how exactly mannan alignment,
including the number of mannose units and the branched motif of LM,
affects protein engagement during host–pathogen interactions.
In this study, we synthesized the exact substructures of the LM glycans
that consist of an α(1,6) mannan core, with and without the
complete α(1,2) mannose branching, and comparatively studied
their protein–carbohydrate interactions. The synthetic LM glycans
were equipped with a thiol linker for immobilizations on the surfaces
of microarrays. As per our findings, the presence of the branching
α(1,2) mannose on the LM glycans increases their binding toward
the dendritic cell-specific intercellular adhesion molecule-3 grabbing
non-integrin receptor. An increase in the number of mannose units
on the glycans also increases the binding with the mannose receptor.
Thus, the set of synthetic glycans can serve as a useful tool to study
the biological activities of LM and can provide a better understanding
of host–pathogen interactions.
Nanoparticles that
modulate innate immunity can act as vaccine
adjuvants and antigen carriers and are promising alternatives to conventional
anticancer therapy. Nanoparticles might, upon contact with serum,
activate the complement system that might in turn result in clearance
and allergic reactions. Herein, we report that ultrasmall glyconanoparticles
decorated with nonimmunogenic α-(1–6)-oligomannans trigger
an innate immune response without drastically affecting the complement
system. These negatively charged glyconanoparticles (10–15
nm) are stable in water and secrete proinflammatory cytokines from
macrophages via the NF-κB signaling pathway. The glyconanoparticles
can be used as immunomodulators for monotherapy or in combination
with drugs and vaccines.
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