The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity

Abstract

The host immune status is critical for preventing opportunistic infections with Candida albicans. Whether the natural fungal diversity that exists between C. albicans isolates also influences disease development remains unclear. Here, we used an experimental model of oral infection to probe the host response to diverse C. albicans isolates in vivo and found dramatic differences in their ability to persist in the oral mucosa, which inversely correlated with the degree and kinetics of immune activation in the host. Strikingly, the requirement of interleukin (IL)-17 signaling for fungal control was conserved between isolates, including isolates with delayed induction of IL-17. This underscores the relevance of IL-17 immunity in mucosal defense against C. albicans. In contrast, the accumulation of neutrophils and induction of inflammation in the infected tissue was strictly strain dependent. The dichotomy of the inflammatory neutrophil response was linked to the capacity of fungal strains to cause cellular damage and release of alarmins from the epithelium. The epithelium thus translates differences in the fungus into qualitatively distinct host responses. Altogether, this study provides a comprehensive understanding of the antifungal response in the oral mucosa and demonstrates the relevance of evaluating intraspecies differences for the outcome of fungal-host interactions in vivo.

Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa

“…This concept of linking fungal pathogenicity to damage was further supported by findings by Schönherr et al in which the virulence of C. albicans clinical isolates was directly correlated with their capacity to induce oral mucosal insult (44). Notably, only the expression of ECE1/Candidalysin was strongly correlated with damage and pathogenesis in several (but not all) C. albicans isolates.…”

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

“…Moreover, IL-1␣ plays a critical role in regulating host resistance in murine models of oral candidiasis (63,64). During oral candidiasis, IL-1␣ is secreted by keratinocytes (64). In contrast, we show that radiosensitive cells, including macrophages, are the major cellular source of IL-1␣ following A. fumigatus challenge (Fig.…”

“…Specifically, the tongue epithelium is highly stratified. Schonherr and colleagues found that the depth of hyphal growth corresponds to IL-1␣ release in the candidiasis model (64). In contrast, the respiratory epithelium can be as thin as a single cell to facilitate gas exchange.…”

“…that were able to undergo hyphal growth induced higher levels of IL-1␣ expression, which were dampened in C. albicans mutants that were defective in hyphal growth (60)(61)(62). Moreover, IL-1␣ plays a critical role in regulating host resistance in murine models of oral candidiasis (63,64). During oral candidiasis, IL-1␣ is secreted by keratinocytes (64).…”

Identification ofCandida albicansregulatory genes governing mucosal infection

“…These results indicate that the mutant strain does not differ from the wild‐type in initial settlement in the tongue but rather in its increased ability to persist in, and/or reduced clearance from, this tissue. The fast clearance of the reference strain in this OPC model is in agreement with previous reports (Conti et al ., ; Schönherr et al ., ). We confirmed that the phenotype of the mutant strain could be ascribed to the specified locus because adding back the corresponding wild‐type copy of the CUP9 gene to the deletion mutant strain resulted in reduced persistence (and/or more efficient clearance; Figure f).…”