Insights into Interactions of Mycobacteria with the Host Innate Immune System from a Novel Array of Synthetic Mycobacterial Glycans

An
array of homogeneous glycans representing all the major carbohydrate
structures present in the cell wall of the human pathogen Mycobacterium tuberculosis and other mycobacteria has been
probed with a panel of glycan-binding receptors expressed on cells
of the mammalian innate immune system. The results provide an overview
of interactions between mycobacterial glycans and receptors that mediate
uptake and survival in macrophages, dendritic cells, and sinusoidal
endothelial cells. A subset of the wide variety of glycan structures
present on mycobacterial surfaces interact with cells of the innate
immune system through the receptors tested. Endocytic receptors, including
the mannose receptor, DC-SIGN, langerin, and DC-SIGNR (L-SIGN), interact
predominantly with mannose-containing caps found on the mycobacterial
polysaccharide lipoarabinomannan. Some of these receptors also interact
with phosphatidyl-myo-inositol mannosides and mannose-containing
phenolic glycolipids. Many glycans are ligands for overlapping sets
of receptors, suggesting multiple, redundant routes by which mycobacteria
can enter cells. Receptors with signaling capability interact with
two distinct sets of mycobacterial glycans: targets for dectin-2 overlap
with ligands for the mannose-binding endocytic receptors, while mincle
binds exclusively to trehalose-containing structures such as trehalose
dimycolate. None of the receptors surveyed bind furanose residues,
which often form part of the epitopes recognized by antibodies to
mycobacteria. Thus, the innate and adaptive immune systems can target
different sets of mycobacterial glycans. This array, the first of
its kind, represents an important new tool for probing, at a molecular
level, biological roles of a broad range of mycobacterial glycans,
a task that has not previously been possible.