Dataset Information

11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking ?-Glucan in Fungal Cell Wall.

ABSTRACT: In the course of optimizing GPI biosynthesis inhibitors, we designed and synthetized a 2-aminonicotinamide derivative named 11g. After evaluating the antifungal activity of compound 11g in vitro, we investigated the influences of 11g on fungi immunogenicity. In addition, we also took advantage of murine systemic candidiasis model to investigate the protective effects of 11g in vivo. Results show that 11g exhibited potent antifungal activity both in vitro and in vivo. Further study shows that 11g caused the unmasking of fungi ?-glucan layer, leading to stronger immune responses in macrophages through Dectin-1. These results suggest that 11g is a very promising antifungal candidate, which assists in eliciting stronger immune responses to help host immune system disposing pathogens. The discovery of 11g might expand the toolbox of fungal infection treatment.

SUBMITTER: Huang X

PROVIDER: S-EPMC7338940 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall.

Huang Xin X Liu Yu Y Ni Tingjunhong T Li Liping L Yan Lan L An Maomao M Zhang Dazhi D Jiang Yuanying Y

Frontiers in microbiology 20200630

In the course of optimizing GPI biosynthesis inhibitors, we designed and synthetized a 2-aminonicotinamide derivative named 11g. After evaluating the antifungal activity of compound 11g in vitro, we investigated the influences of 11g on fungi immunogenicity. In addition, we also took advantage of murine systemic candidiasis model to investigate the protective effects of 11g in vivo. Results show that 11g exhibited potent antifungal activity both in vitro and in vivo. ...[more]

PMID: 32695076

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Project description:Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host's immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (STE11ΔN467) induced unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by ≥33 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked STE11ΔN467 mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11ΔN467 allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11ΔN467-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11ΔN467 cells. In an effort to understand the mechanism by which Ste11ΔN467 causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor CPH1 and the cell wall sensor DFI1. In this report we show that a cph1ΔΔ mutation restored ß(1,3)-glucan exposure to wild-type levels in the STE11ΔN467 strain, confirming that Cph1 is the transcription factor mediating Ste11ΔN467-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11ΔN467 is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11ΔN467-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11ΔN467, Dfi1 activates a parallel signaling pathway that is involved in Ste11ΔN467-induced unmasking.

Project description:Microbial interactions represent an understudied facet of human health and disease. In this study, the interactions that occur between Chlamydia trachomatis and the opportunistic fungal pathogen, Candida albicans were investigated. Candida albicans is a common component of the oral and vaginal microbiota responsible for thrush and vaginal yeast infections. Normally, Candida exist in the body as yeast. However, disruptions to the microbiota create conditions that allow expanded growth of Candida, conversion to the hyphal form, and tissue invasion. Previous studies have shown that a myriad of outcomes can occur when Candida albicans interacts with pathogenic bacteria. To determine if C. trachomatis physically interacts with C. albicans, we incubated chlamydial elementary bodies (EB) in medium alone or with C. albicans yeast or hyphal forms for 1 h. Following incubation, the samples were formaldehyde-fixed and processed for immunofluorescence assays using anti-chlamydial MOMP or anti- chlamydial LPS antibodies. Replicate samples were replenished with culture medium and incubated at 35°C for 0-120 h prior to fixation for immunofluorescence analysis or collection for EB infectivity assays. Data from this study indicates that both C. trachomatis serovar E and C. muridarum EB bind to C. albicans yeast and hyphal forms. This interaction was not blocked by pre-incubation of EB with the Candida cell wall components, mannan or ?-glucans, suggesting that EB interact with a Candida cell wall protein or other structure. Bound EB remained attached to C. albicans for a minimum of 5 days (120 h). Infectivity assays demonstrated that EB bound to C. albicans are infectious immediately following binding (0h). However, once bound to C. albicans, EB infectivity decreased at a faster rate than EB in medium alone. At 6h post binding, 40% of EB incubated in medium alone remained infectious compared to only 16% of EB bound to C. albicans. Likewise, pre-incubation of EB with laminarin, a soluble preparation of ?-glucan, alone or in combination with other fungal cell wall components significantly decreases chlamydial infectivity in HeLa cells. These data indicate that interactions between EB and C. albicans inhibit chlamydial infectivity, possibly by physically blocking EB interactions with host cell receptors.

Dataset Information

11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking ?-Glucan in Fungal Cell Wall.

Publications

11g, a Potent Antifungal Candidate, Enhances <i>Candida albicans</i> Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall.

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