Candida-bacterial cross-kingdom interactions

Abstract

While the fungus Candida albicans is a common colonizer of healthy humans, it is also responsible for mucosal infections and severe invasive disease. Understanding the mechanisms that allow C. albicans to exist as both a benign commensal and as an invasive pathogen have been the focus of numerous studies, and recent findings indicate an important role for cross-kingdom interactions on C. albicans biology. This review highlights how C. albicans-bacteria interactions influence healthy polymicrobial community structure, host immune responses, microbial pathogenesis, and how dysbiosis may lead to C. albicans infection. Finally, we discuss how cross-kingdom interactions represent an opportunity to identify new antivirulence compounds that target fungal infections.

Keywords: Candida albicans; antifungal immunity; cross-kingdom interactions; polymicrobial infection.

Figure 1.. Candida interacts with bacteria and immune cells in the healthy gastrointestinal tract.

Candida-bacteria interactions begin in infancy and persist into adulthood, influencing Candida growth and colonization as well as interactions with host immune cells. (a) Summary of Candida-bacteria interactions in the developing infant gut. In pre-term infants, Staphylococcus species (spp.) inhibit Candida albicans colonization, and C. albicans inhibits Escherichia and Klebsiella spp. colonization. As the microbiota mature, Lactobacillus spp. and Bifidobacteria colonize, and the colonization of these organisms is negatively correlated with C. albicans colonization. (b) Summary of Candida-bacteria and Candida-host interactions in the adult gastrointestinal tract. Microbiota-derived secondary metabolites such as bile acids and short chain fatty acids (SCFA) inhibit C. albicans growth and hyphal formation. Colonization of Bacteroides species stimulates production of a mucus layer that C. albicans also colonizes. C. albicans may benefit from sugars produced via B. thetaiotaomicron breakdown of mucins, while Bacteroides may benefit from Candida cell wall mannans and a hypoxic microenvironment created by C. albicans growth. C. albicans colonization also regulates antifungal immunity through Th17 cells and CX3CR1⁺ phagocytes that express CARD9. Th17 cells produce IL-17 and IL-22 that coordinates neutrophil (PMN)-mediated protection against C. albicans and S. aureus disseminated infection. CX3CR1⁺ cells induce production of anti-Candida IgG antibodies.

Figure 2.. Mucosal dysbiosis can initiate or enhance Candida pathogenesis in the gut.

Delivery of vancomycin or ß-lactam antibiotics enhance C. albicans virulence through disparate mechanisms. Vancomycin disrupts immune cell-mediated gastrointestinal barrier function, which allows for translocation of the gut microbiota into the bloodstream. This introduces a mixed fungal-bacterial infection when C. albicans enters the bloodstream, enhancing mortality. ß-lactams result in the mass release of bacterial peptidoglycan (PG) cell wall fragments, which are potent hyphal-inducing signals for C. albicans and result in greater C. albicans dissemination to the bloodstream. As C. albicans translocates through and invades the epithelial barrier, production of the secreted toxin candidalysin enhances epithelial damage. Secreted IgA binds C. albicans hyphal, but not yeast, adhesins, and plays an important role in preventing hyphal-mediated damage in the gastrointestinal tract.

Figure 3.. Mechanisms of cross-kingdom interactions between Candida and bacteria that alter pathogenesis.

Different in vitro, in vivo, and clinical studies demonstrate synergistic and antagonistic interactions between Candida and bacterial species. Cross-kingdom interactions can modulate host health and influence disease progression in diverse biological systems. (a) C. albicans and S. mutans form interkingdom assemblages in human saliva and show “leaping-” and “walking-like” mobility in the oral cavity, which cause biofilm growth and tooth decay. (b) C. albicans and Gram-positive bacteria can cause bloodstream infections (BSI) and increase mortality during co-infection. (c) Lactobacillus species show antagonistic relationships with C. albicans isolates and inhibit morphogenesis and biofilm-related genes during recurrent vulvovaginal candidiasis (RVVC). (d) C. albicans adhesins Als1p and Als3p facilitate hyphal binding to S. aureus and mediate staphylococcal dissemination in a murine oral infection model. (e) H. pylori can reside within C. albicans vacuoles and be protected from antibiotic and oxidative stress during gastritis. (f) C. albicans augments staphylococcal virulence by agr-associated increased toxin production during intra-abdominal co-infection in mice. (g) Ethanol produced by C. albicans induces the production of 5-methyl-phenazine-1-carboxylic acid (5-MPCA) in P. aeruginosa, which exhibits antifungal activity. P. aeruginosa quorum sensing molecule N-(3-Oxidodecanoyl)-L-homoserine lactone (C12AHL) can induce azole resistance in C. albicans. (h) Candida induces hemolysin production by P. mirabilis which increases enterocyte damage in vitro.