Candida albicans commensalism in the oral mucosa is favoured by limited virulence and metabolic adaptation

Abstract

As part of the human microbiota, the fungus Candida albicans colonizes the oral cavity and other mucosal surfaces of the human body. Commensalism is tightly controlled by complex interactions of the fungus and the host to preclude fungal elimination but also fungal overgrowth and invasion, which can result in disease. As such, defects in antifungal T cell immunity render individuals susceptible to oral thrush due to interrupted immunosurveillance of the oral mucosa. The factors that promote commensalism and ensure persistence of C. albicans in a fully immunocompetent host remain less clear. Using an experimental model of C. albicans oral colonization in mice we explored fungal determinants of commensalism in the oral cavity. Transcript profiling of the oral isolate 101 in the murine tongue tissue revealed a characteristic metabolic profile tailored to the nutrient poor conditions in the stratum corneum of the epithelium where the fungus resides. Metabolic adaptation of isolate 101 was also reflected in enhanced nutrient acquisition when grown on oral mucosa substrates. Persistent colonization of the oral mucosa by C. albicans also correlated inversely with the capacity of the fungus to induce epithelial cell damage and to elicit an inflammatory response. Here we show that these immune evasive properties of isolate 101 are explained by a strong attenuation of a number of virulence genes, including those linked to filamentation. De-repression of the hyphal program by deletion or conditional repression of NRG1 abolished the commensal behaviour of isolate 101, thereby establishing a central role of this factor in the commensal lifestyle of C. albicans in the oral niche of the host.

Fungal gut microbiota dysbiosis in systemic lupus erythematosus

“…We also identified the changes in SLE-specific fungal composition, including the obvious enrichment of Candida of Ascomycota phylum and the loss of Malassezia of Basidiomycota phylum, implying their potential role in the pathogenesis of SLE and deserving further investigation. Candida is an important opportunistic pathogenic fungus ( Witchley et al, 2019 ) and human symbiotic fungi in the gastrointestinal tract ( Alonso-Monge et al, 2021 ; McDonough et al, 2021 ), oral cavity ( Millet et al, 2020 ; Lemberg et al, 2022 ), and vagina ( Jang et al, 2019 ; Alvendal et al, 2020 ). The excessive growth of Candida is associated with a variety of diseases, including thrush ( Salvatori et al, 2016 ) and vaginal candidiasis.…”

In vitro and in vivo Characterization of Host–Pathogen Interactions of the L3881 Candida albicans Clinical Isolate

“…SC5314 has been widely acknowledged as a virulent lineage in mouse models, and since its isolation, it has been used as a wild-type reference in previous studies ( Padovan et al, 2009 ; Lionakis et al, 2011 ; Maza et al, 2017 ; Shankar et al, 2020 ; Lemberg et al, 2022 ). In turn, the studies that employed L3881 (first described as L757 lineage, Padovan et al, 2009 ) have not yet reached a conclusion about its virulence status.…”

“…Candida albicans is a human commensal fungus and the etiologic agent of infections in skin, oral and esophageal cavities, gastrointestinal tract, lungs, and bloodstream in immunocompromised individuals ( Kadosh and Lopez-Ribot, 2013 ; Lemberg et al, 2022 ). Although it is considered an opportunistic fungus, C. albicans is the most common cause of nosocomial fungal infections, with a mortality rate of ∼40% in patients with systemic infections ( Gudlaugsson et al, 2003 ; Perlroth et al, 2007 ; Erami et al, 2022 ; Jeong et al, 2022 ).…”

RFX transcription factor in the human‐associated yeast Candida albicans regulates adhesion to oral epithelium

“…Multiple fungal and host factors contribute to C. albicans colonization of the oral mucosa and oropharyngeal candidiasis. On the fungus side, these include adhesins such as hyphal wall protein 1 (Hwp1) and agglutinin‐like sequence (Als) proteins (Martin et al., 2011; Murciano et al., 2012; Naglik et al., 2006; Staab et al., 1999); candidalysin, a secreted fungal peptide toxin (Moyes et al., 2016); regulators of biofilm formation (Solis et al., 2022); endocytosis factors (Naseem et al., 2019); and metabolic adaptations (Lemberg et al., 2022), among others. On the host side, oral epithelial cells respond to the infection by secreting antimicrobial peptides that directly kill the fungus and by releasing pro‐inflammatory cytokines that recruit neutrophils to the site of infection, where they can destroy C. albicans and limit the extent of epithelial cell damage (Swidergall & Filler, 2017; Trautwein‐Weidner et al., 2015; Weindl et al., 2007).…”

“…endocytosis factors (Naseem et al, 2019); and metabolic adaptations (Lemberg et al, 2022), among others. On the host side, oral epithelial cells respond to the infection by secreting antimicrobial peptides that directly kill the fungus and by releasing pro-inflammatory cytokines that recruit neutrophils to the site of infection, where they can destroy C. albicans and limit the extent of epithelial cell damage (Swidergall & Filler, 2017;Trautwein-Weidner et al, 2015;Weindl et al, 2007).…”