Investigation of immunological potential and chemical properties of yeast cell surface polysaccharides

Abstract

Yeast is a constituent of mammalian commensal microorganisms, which has a similar potential to symbiotic bacteria that mutually interacting with multiple host and yeast cell derived molecules such as cell wall polysaccharides retain immunomodulatory capability. β-Glucan is the one of the major constituent of the fungal cell wall polysaccharides and reported to shape immune responses. Numerous studies have demonstrated that yeast cell wall derived β-glucan promote pro-inflammatory responses and they have been utilized in clinics as adjuvant for therapies against cancer and microbial infection. On the other hand, a relatively fewer studies also suggest an anti-inflammatory role of β-glucan in immune responses. Similarly to fungal β-glucan, fungal derived mannan is also reported to have immunomodulatory potential. However, although roles of yeast derived polysaccharides in immune modulation have been reported, functional properties of yeast derived immunoregulatory molecule and underlined mechanisms by which fungal derived immunological active molecule orchestrate the immune responses remain largely unknown. In this study, I aimed to systemically dissect the immunological roles of polysaccharide components derived from yeast cell wall in health and disease and establish molecular mechanism(s). To this end, I utilized zymosan and purified yeast extract for the study as they present polysaccharide components of yeast cell wall. In the first part of this study, I demonstrated the proinflammatory potential of yeast cell wall derived β-1,3-glucan which is dominant polysaccharide of yeast cell wall and enhances antitumor immunity. In the second part, I identified potent immunoregulatory yeast cell surface polysaccharides and characterized their chemical specificities. Mannan and β-1,6-glucan are relatively less abundant polysaccharides of yeast cell wall and exposed upon removal of β-1,3-glucan by enzymatic depletion or polysaccharide purifying techniques. Mannan/β-1,6-glucan containing polysaccharides potentiate anti-inflammatory effects and suppress autoimmune inflammatory disorders. In accordance with their composition, I named these immunoregulatory polysaccharide mixture as MGCP. In the last part, I established underlying mechanism(s) by which MGCP modulates immune responses and tested applicability of MGCP to multiple inflammatory autoimmune disorders. MGCP is capable of exerting anti-inflammatory potential and suppressing multiple inflammatory disorders through two independent mechanisms mediating on dendritic cells (DCs), in one hand by facilitating differentiation of regulatory T cells (Treg) dependent on Dectin1-Cox2 signaling axis and the other hand by suppressing induction of deleterious T helper 1 response through TLR2 dependent mechanism. As a result, this study elucidates the functional specificities of yeast cell wall derived polysaccharides and ascertains their roles in the context of pro- and anti-inflammatory immune responses. Furthermore, by identifying yeast cell wall derived MGCP as a potent immunomodulatory component that is effective against multiple experimental autoimmune diseases, I expect to extend these findings towards potential therapeutic relevance.