Controlling Candida: immune regulation of commensal fungi in the gut

Abstract

The intestinal microbiome harbors fungi that pose a significant risk to human health as opportunistic pathogens and drivers of inflammation. Inflammatory and autoimmune diseases are associated with dysbiotic fungal communities and the expansion of potentially pathogenic fungi. The gut is also the main reservoir for disseminated fungal infections. Immune interactions are critical for preventing commensal fungi from becoming pathogenic. Significant strides have been made in defining innate and adaptive immune pathways that regulate intestinal fungi, and these discoveries have coincided with advancements in our understanding of the fungal molecular pathways and effectors involved in both commensal colonization and pathogenesis within the gut. In this review, we will discuss immune interactions important for regulating commensal fungi, with a focus on how specific cell types and effectors interact with fungi to limit their colonization or pathogenic potential. This will include how innate and adaptive immune pathways target fungi and orchestrate antifungal immune responses, in addition to how secreted immune effectors, such as mucus and antimicrobial peptides, regulate fungal colonization and inhibit pathogenic potential. These immune interactions will be framed around our current understanding of the fungal effectors and pathways regulating colonization and pathogenesis within this niche. Finally, we highlight important unexplored mechanisms by which the immune system regulates commensal fungi in the gut.

Keywords: Candida; Candida albicans; gut microbiota; microbiome; mucosal immunity; mycobiome.

FIG 1

Immune regulation of fungal colonization. The first line of defense against C. albicans colonization and pathogenesis is mediated by the epithelial layer. Mucin produced by goblet cells (green) acts as a barrier to fungal colonization and potentially directly inhibits hyphae formation. Tight junctions between IECs block fungal entry, while AMP production by IECs and Paneth cells (red) limits fungal growth through fungicidal effects. Tissue resident and infiltrating innate immune cells orchestrate the immune response by patrolling the LP for fungal barrier disruption. In response to proinflammatory cytokine response by resident MNPs and T cells, infiltrating neutrophils limit fungal dissemination by phagocytosis and production of NETs and antifungal effector molecules. CX3CR1⁺ CARD9⁺ MNPs and cDC2s phagocytize invading hyphae or sample luminal fungi via M cell endocytosis (not pictured) or directly through tight junctions (cDCs only). Activated MNPs produce proinflammatory cytokines and initiate the adaptive immune response through interactions with B and T cells in local GALT or draining lymph nodes. Secretory IgA primarily targeting hyphal cells is produced by plasma cells and transported into intestinal lumen by pIgR-mediated transcytosis (not pictured). IL-17 and IL-22 produced by Th17 cells and other innate T cells activate the production of AMPs by epithelial cells and promote barrier function limiting fungal and bacterial colonization. Direct IL-17A binding to Candida in the gut lumen potentially impacts colonization by altering the transcriptional profile.

FIG 2

How immune-targeted Candida processes regulate commensal colonization of the intestine. Several C. albicans transcription factors that promote or enhance filamentation (formation of hyphae) reduce competitive fitness within mouse colonization models, whereas transcription factors that limit filamentation enhance fitness. Expression of adhesin-associated virulence factors, Hyr1, Als3, and Sap6 reduces fitness within the intestine, while ECE1, encoding candidalysin, enhances fitness. Regulators of cell wall composition and cell wall stress response also impact C. albicans fitness within the murine gut.