Fig. 4. Structures of natural zwitterionic polysaccharides and their proposed mechanism of action.

a | Structures of natural zwitterionic polysaccharides (ZPSs) PS A1, PS A2 and PS B from Bacteroides fragilis¹⁹¹. b,c | Structures of natural ZPSs from Streptococcus pneumoniae (type 1, Sp 1, panel b) and Staphylococcus aureus (type 5, CP5, and type 8, CP8, panel c)²⁰². d | Schematic representation of the proposed model for ZPS mechanism of action and crosstalk between innate and adaptive immune compartments²¹⁵. Within the innate immunity context (left), Toll-like receptor 2 (TLR2)-mediated recognition of zwitterionic polysaccharide induces the activation of the myeloid differentiation factor 88 (MyD88)-dependent pathway in antigen-presenting cells (e.g. dendritic cells), leading to NF-κB-dependent pro-inflammatory cytokine expression (tumour necrosis factor (TNF), interleukin-12 (IL-12)), NO production, and MHC class II (MHC-II) and co-stimulatory molecule expression and upregulation. Adaptive immunity events (right) involving interaction between T cell receptor (TCR) and processed ZPSs presented on MHC-II, along with co-stimulation via CD86/CD28 and IL-12/IL-12R interactions, ultimately trigger ZPS-activated CD4⁺ T cells to produce the T helper 1 (T_H1) cytokine interferon-γ (IFNγ). DC, dendritic cell. Part d adapted with permission from ref.²¹⁵, Rockefeller University Press.