New Role of P. brasiliensis α-Glucan: Differentiation of Non-conventional Dendritic Cells

Abstract

The cell wall has a critical role in the host immune response to fungal pathogens. In this study, we investigated the influence of two cell wall fractions of the dimorphic fungi Paracoccidioides brasiliensis (Pb) in the in vitro generation of monocyte-derived dendritic cells (MoDCs). Monocytes were purified from the peripheral blood of healthy donors and cultivated for 7 days in medium supplemented with IL-4 and GM-CSF in the presence of Pb cell wall fractions: the alkali-insoluble F1, constituted by β-1,3-glucans, chitin and proteins, and the alkali-soluble F2, mainly constituted by α-glucan. MoDCs phenotypes were evaluated regarding cell surface expression of CD1a, DC-SIGN, HLA-DR, CD80, and CD83 and production of cytokines. The α-glucan-rich cell wall fraction downregulated the differentiation of CD1a+ MoDCs, a dendritic cell subset that stimulate Th1 responses. The presence of both cell fractions inhibited DC-SIGN and HLA-DR expression, while the expression of maturation markers was differentially induced in CD1a– MoDCs. Differentiation upon F1 and F2 stimulation induced mixed profile of inflammatory cytokines. Altogether, these data demonstrate that Pb cell wall fractions differentially induce a dysregulation in DCs differentiation. Moreover, our results suggest that cell wall α-glucan promote the differentiation of CD1a– DCs, potentially favoring Th2 polarization and contributing to pathogen persistence.

Paracoccidioidomycosis Protective Immunity

“…The in vitro differentiation of human monocyte-derived dendritic-cell subpopulations is influenced by the presence of Paracoccidioides cell wall fractions such as the alkali-insoluble β-glucan-rich fraction and the alkali-soluble α-glucan-rich fraction. The α-glucan fraction stimulates the differentiation of a dendritic-cell subpopulation that, through the secretion of cytokines, can negatively affect polarization towards Th1 immune response and play a role enhancing fungal pathogenesis [ 53 ]. The existence of different dendritic cell subpopulations and their various activation pathways have already been mentioned as well as the different cytokines and T cell subpopulations that these APCs will elicit.…”

The Trojan Horse Model in Paracoccidioides: A Fantastic Pathway to Survive Infecting Human Cells

“…Two cell wall fractions, one constituted mainly by α-glucan and other by β-(1,3)-glucans, chitin, and proteins and the alkali-soluble were investigated, demonstrating the induction of a dysregulation in DCs differentiation. Paracoccidioides cell wall α-glucan, presented as the mayor neutral polysaccharide in the yeast phase, also influences favoring Th2 polarization and contributes to pathogen persistence ( Puccia et al., 2011 ; Souza et al., 2019 ). On the other hand, the lower efficiency of DCs from mice susceptible to P. brasiliensis in inducing a Th1 response was observed, an effect that could be related to the progression of the disease in vivo ( Almeida and Lopes, 2001 ).…”

Monocyte-Derived Dendritic Cells Can Revert In Vitro Antigen-Specific Cellular Anergy in Active Human Paracoccidioidomycosis

“…On cutaneous lesions from patients with PCM, Langerhans cells were shown to be in reduced numbers, and the presence of factor XIIIa+ dermal dendrocytes, dermal DCs and plasmacytoid DCs was also reported [ 19 , 20 , 21 , 22 ]. Some reports demonstrated relevant effects of P. brasiliensis on monocyte-derived dendritic cells (moDCs) from healthy donors, especially on innate immunity mechanisms [ 23 , 24 , 25 , 26 ], but few investigated these cells from patients with PCM [ 27 , 28 ].…”