In vitro evaluation of Innate immunity effects on Candida glabrata cell wall properties and host-pathogen interactions

Human fungal infections vary from other microbial infections in many aspects, o wing to their highly varied disposition and infectivity against a wide range of human cell types. Candida species are the leading cause of invasive candidiasis with Candida glabrata being the second most frequently isolated Candida species from intensive care unit patients. Candida glabrata is an opportunistic pathogen that causes a wide range of infections, often linked to antifungal resistance. Efforts to develop new antifungals have struggled to keep up with rising resistance, a major concern for clinicians. During infection, C. glabrata interacts with innate immune cells like macrophages, monocytes, and neutrophils, which serve as the first line of defense. It has been shown that C. glabrata can survive and even proliferate inside macrophages, producing relatively minimal impact on immunological response and cytokine production. This study concentrated on the C. glabrata cell wall, as fungal cell wall is the primary site of contact with host cells of the innate immune system. Exposure of human THP-1 macrophages impacted on C glabrata cell wall biochemistry, biophysical cell wall properties, antifungal susceptibility as well as impact on immune response and recognition. Upon exposure to THP-1 macrophages, the cell wall architecture of C. glabrata was modulated, demonstrated by a reduction in the B-glucan and chitin layers, along with an increase in the mannan layer. The increase in the mannan layer led to alterations in cell surface hydrophobicity, cell adhesion, and cell wall porosity of C. glabrata. Moreover, the increase in the mannan layer shielded the fungus from antifungal treatment, contributing to its protection and concealment. This led to a significant enhancement of antifungal resistance in C. glabrata upon exposure to THP-l macrophages. In addition, the immune response and recognition upon macrophage exposure was subsequently explored using human magnetic Luminex assay for the cytokine quantification, flow cytometry analysis for the phagocytosis assay as well as CFU counting for the killing assay. Collectively, data from both phagocytosis and killing assays demonstrated that exposure to human THP- I macrophages made C. glabrata more pathogenic and harder to be killed, due to the cell wall modifications.

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