Monosialotetrahexosylganglioside (GM1 ganglioside) (GM1)

The human innate immune receptors modulated by the LTh adjuvant primarily center on the GM1 ganglioside (monosialotetrahexosylganglioside), which serves as the high-affinity binding site for the B-subunit of the heat-labile enterotoxin (LT) from human-origin Escherichia coli. Beyond direct binding to GM1, the LTh adjuvant and its detoxified derivatives, such as LTh(αK) (also known as AD17002), modulate a broader network of innate immune receptors, including Toll-like receptors (TLR2 and TLR4) and NOD2. This modulation occurs through the internalization of the toxin-receptor complex, which triggers mitochondrial stress and the compartmentalized enhancement of type I interferon signaling in the respiratory or mucosal epithelium. The activation of these pathways leads to the maturation of dendritic cells and other antigen-presenting cells, characterized by the upregulation of co-stimulatory molecules like CD80 and CD86 and the secretion of pro-inflammatory cytokines such as IL-12 and IFN-gamma. These innate signals are crucial for bridging to the adaptive immune system, where they promote the differentiation of Th1, Th2, and Th17 cells and the production of robust systemic IgG and mucosal IgA antibodies. LTh-based adjuvants are currently being developed for use in intranasal vaccines against respiratory infections, including influenza and COVID-19, and are also explored for their potential to modulate immune responses in allergic diseases and cancer immunotherapy.

Other names

MonosialotetrahexosylgangliosideHeat-labile enterotoxin receptorLT receptorGM1 gangliosideHuman innate immune receptors modulated by LTh adjuvant

LTh(αK) binds to GM1 ganglioside on the surface of epithelial and immune cells, leading to internalization and induction of mitochondrial stress and type I interferon signaling. It also modulates TLR2, TLR4, and NOD2 pathways, promoting dendritic cell maturation and enhancing Th1/Th2/Th17 adaptive immune responses.