Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: Chemical synthesis and functional studies

Abstract

Chemistry-based investigation is reviewed which led to identification of the active entities responsible for the immunostimulating potencies of peptidoglycan and lipopolysaccharide. Though these glycoconjugates which ubiquitously occur in wide range of bacteria as the essential components of their cell envelopes have long been known to enhance the immunological responses of higher animals, neither the precise chemical structures required nor the mechanism of their action remained to be elucidated until early 1970s. Chemical synthesis of partial structures of peptidoglycan proved N-acetylmuramyl-L-alanyl-D-isoglutamine to be the minimum structure responsible for the activity and led to later identification of its receptor protein Nod2 present in animal cells. Another active partial structure of peptidoglycan, γ-D-glutamyl-meso-diaminopimelic acid, and its receptor Nod1 were also identified as well. With regard to lipopolysaccharide, its glycolipid part named lipid A was purified and the structure studied. Chemically synthesized lipid A according to the newly elucidated structure exhibited full activity described for lipopolysaccharide known as endotoxin. Synthetic homogeneous lipid A and its structural analogues and labeled derivatives enabled precise studies of their interaction with receptor proteins and the mechanism of their action. Chemical synthesis of homogeneous partial structures of peptidoglycan and lipopolysaccharide gave unequivocal evidences for the concept that definite small molecular parts of these complex macromolecular bacterial glycoconjugates are specifically recognized by their respective receptors and trigger our defense system now widely recognized as innate immunity.

LPS remodeling is an evolved survival strategy for bacteria

“…LPS has three structural regions: O-antigen, core, and lipid A. Lipid A is the biologically active component of LPS recognized by the innate immune system (8). Gram-negative bacteria with both environmental and mammalian reservoirs can synthesize modified forms of lipid A in response to environmental stimuli and temperature change (1,6,7).…”

Synthesis and Functional Study of Bacterial Glycoconjugates Triggering the Innate Immune System of Higher Animals

“…TLR4 on the cell membrane in combination with another smaller protein MD2 recognizes lipid A and transfer the signal into the cell (43). Our synthetic pure lipid A, its structural analogues and radio-labeled derivatives were utilized for the analysis how lipid A molecule is recognized by its receptor (3,43). Thanks to recent successful crystallographic investigations, the detailed pictures are now available on the manner of interactions between the receptors and lipid A analogues (44).…”

“…Our novel preparative route to pyranosidic Kdo from D-mannose previously designed was used with a little modification for supply of sufficient materials for the synthesis (38,39). Regio-and α-selective formation of ketosidic linkages of Kdo was accomplished by the use of The synthetic route to 5 was designed on the basis of our knowledge accumulated during the synthetic works on lipid A (3,20,25,26). The 4'-phosphate was introduced after the coupling of the first Kdo with the glucosamine disaccharide since the presence of a protected 4'-phosphate proved to inhibit coupling with Kdo.…”

“…We thereby anticipated a general defense mechanism of higher animals, where ubiquitous, typical bacterial cell components are recognized as alarm signals of infection and trigger the host system against invading microbes. As the result, definite structures essential for the immunostimulating actions of both PGN and LPS were unequivocally determined (3).…”

Peptidoglycan as Nod1 ligand; fragment structures in the environment, chemical synthesis, and their innate immunostimulation

“…[96][97][98] More recently, the roles of Nod1 and other NLR in T cell responses have also been documented. [99][100][101][102] Nod1 and Nod2 ligands significantly enhance the induction of dendritic cell (DC)-mediated cross-priming of antigen-specific CD 8+ T cells.…”