Augmented Enterocyte Damage During Candida albicans and Proteus mirabilis Coinfection

Abstract

The human gut acts as the main reservoir of microbes and a relevant source of life-threatening infections, especially in immunocompromised patients. There, the opportunistic fungal pathogen Candida albicans adapts to the host environment and additionally interacts with residing bacteria. We investigated fungal-bacterial interactions by coinfecting enterocytes with the yeast Candida albicans and the Gram-negative bacterium Proteus mirabilis resulting in enhanced host cell damage. This synergistic effect was conserved across different P. mirabilis isolates and occurred also with non-albicans Candida species and C. albicans mutants defective in filamentation or candidalysin production. Using bacterial deletion mutants, we identified the P. mirabilis hemolysin HpmA to be the key effector for host cell destruction. Spatially separated coinfections demonstrated that synergism between Candida and Proteus is induced by contact, but also by soluble factors. Specifically, we identified Candida-mediated glucose consumption and farnesol production as potential triggers for Proteus virulence. In summary, our study demonstrates that coinfection of enterocytes with C. albicans and P. mirabilis can result in increased host cell damage which is mediated by bacterial virulence factors as a result of fungal niche modification via nutrient consumption and production of soluble factors. This supports the notion that certain fungal-bacterial combinations have the potential to result in enhanced virulence in niches such as the gut and might therefore promote translocation and dissemination.

Escherichia coli Nissle 1917 Antagonizes Candida albicans Growth and Protects Intestinal Cells from C. albicans-Mediated Damage

“…Our findings that EcN exerts growth-inhibitory activity against Ca when both species are interacting together led us to test whether EcN is capable of inhibiting C. albicans ’ ability to cause damage to intestinal cells. We used a relevant human intestinal epithelial cell model composed of brush border-forming C2BBe1 cells and mucus-secreting HT29-MTX cells at a 70:30 ratio, respectively [ 24 ]. This model was shown as a versatile and suitable in vitro model of the human intestinal epithelium [ 27 ].…”

“…The human colonic adenocarcinoma cell line C2BBe1 (CRL-2102™, ATCC; RRID:CVCL_1096) and mucus-secreting HT29-MTX cells (HT29-MTXE12, Sigma, Roedermark, Germany; RRID: CVCL_G356) were cultivated in high-glucose DMEM (Gibco) supplemented with 10% heat-inactivated fetal calf serum (FCS), 0.01 mg/mL holo-transferrin (Merck) and 1% non-essential amino acids (Gibco) and maintained at 37 • C, 5% CO 2 [24]. The cells were washed with PBS pH 7.4 and then detached via accutase digestion for C2BBe1 and trypsin for HT29-MTX for 10 min at 37 • C. The cell number was determined using a Neubauer chamber by counting a 1:2 mixture of cells with trypan blue, which stains only dead cells.…”

“…Lactobacillus rhamnosus in particular can antagonize Ca by reshaping the metabolic environment, forcing metabolic adaptations that reduce Ca pathogenicity [ 23 ]. On the other hand, certain fungal–bacterial combinations—for example, C. albicans and Proteus mirabilis —have the potential to result in enhanced virulence and might, therefore, promote Ca translocation and dissemination from the gastrointestinal tract [ 24 ]. In this report, we investigated the interaction between Ca and probiotic strain EcN.…”