Mannan Molecular Substructures Control Nanoscale Glucan Exposure in Candida

Abstract

SUMMARY Cell wall mannans of Candida albicans mask β-(1,3)-glucan from recognition by Dectin-1, contributing to innate immune evasion. Glucan exposures are predominantly single receptor-ligand interaction sites of nanoscale dimensions. Candida species vary in basal glucan exposure and molecular complexity of mannans. We used super-resolution fluorescence imaging and a series of protein mannosylation mutants in C. albicans and C. glabrata to investigate the role of specific N-mannan features in regulating the nanoscale geometry of glucan exposure. Decreasing acid labile mannan abundance and α-(1,6)-mannan backbone length correlated most strongly with increased density and nanoscopic size of glucan exposures in C. albicans and C. glabrata, respectively. Additionally, a C. albicans clinical isolate with high glucan exposure produced similarly perturbed N-mannan structures and elevated glucan exposure geometry. Thus, acid labile mannan structure influences the nanoscale features of glucan exposure, impacting the nature of the pathogenic surface that triggers immunoreceptor engagement, aggregation, and signaling.

Dectin-1 Molecular Aggregation and Signaling is Sensitive to β-Glucan Structure and Glucan Exposure on Candida albicans Cell Walls

“…In order to show Dectin-1 aggregation occurs during fungal cell recognition, we used high (TRL035) and low (SC5314) β-glucan exposing C. albicans strains and examined Dectin-1 aggregation occurring at the contact sites with these yeast. TRL035 has been previously shown to have high glucan exposure compared to SC5314 [65]. In addition, our representative images show TRL035 forming a phagocytic cup more efficiently then SC5314 (Fig.…”

“…To determine if this phenomenon occurs at early time points of fungal recognition, we conducted FLIM-FRET experiments of contact sites of C. albicans lab strain SC5314 and our clinical isolate TRL035. TRL035 has been previously described as having higher glucan exposure compared to SC5314 due to a 3-fold reduction of mannan structure [65]. Our results indicate an increase in Dectin-1A aggregation at the contact sites of yeast that have higher glucan exposure as well as contacts with particulate glucan.…”

Diagnostic value of Candida mannan antigen and anti‐mannan IgG and IgM antibodies for Candida infection

“…The Candida cell wall can be divided into two layers. The outer layer is primarily composed of O‐linked and N‐linked glycoproteins, of which 80%‐90% are mannan proteins, and the inner layer is composed of β‐1,3/1,6 glucan . As an important component of the Candida cell wall, mannan is present in C .…”

“…The outer layer is primarily composed of O-linked and N-linked glycoproteins, of which 80%-90% are mannan proteins, and the inner layer is composed of β-1,3/1,6 glucan. 18 As an important component of the Candida cell wall, mannan is present in C. albicans and other Candida species, but the mannan in different species of Candida has different specific structures and is present in different amounts. 19 Studies have shown that the mannan has a higher specificity for invasive Candida infection than anti-mannan.…”

RHOA mediated mechanical force generation through Dectin-1

“…Initial pathogen capture is likely dominated by interactions between abundant cell wall surface mannans and immunoreceptors with relevant binding specificities (e.g., DC-SIGN, CD206). However, Dectin-1 mediated phagocytosis requires this receptor to find its much more sparsely exposed ligand on the cell wall (i.e., nanoscale glucan exposures) 37 . We propose that sparse Dectin-1/glucan interactions may be rate limiting for phagocytosis in physiologically relevant settings.…”