Candida albicans Morphogenesis Is Not Required for Macrophage Interleukin 1β Production

The interaction of Candida albicans with macrophages induces the production of interleukin 1 beta (IL-1 beta) through inflammasome activation in a process that is required for host survival. C. albicans hypha formation has been linked to IL-1 beta production, but the question of whether hyphae are sufficient to trigger IL-1 beta production has not been examined directly. To address this question, a C. albicans library of 165 transcription factor deletion mutants was screened for strains with altered IL-1 beta production by lipopolysaccharide (LPS)-primed J774 cells, a murine macrophage-like cell line. Eight mutants with decreased and two mutants with increased IL-1 beta secretion were identified. In addition, 12 mutants with previously identified morphology deficits were found to induce IL-1 beta secretion to levels similar to those of the wild type. Examination of the morphology of both low and normal IL-1 beta-inducing mutants in macrophages revealed that two mutants (upc2 Delta/upc2 Delta and ahr1 Delta/Delta mutants) were indistinguishable from the wild type with respect to morphology yet induced low levels of IL-1 beta; conversely, the ndt80 Delta/Delta mutant was deficient for hypha formation but induced levels of IL-1 beta similar to those of the wild type. Transcription factor mutants deficient for IL-1 beta secretion also caused markedly lower levels of macrophage lysis. Similarly, the ability of a mutant to cause macrophage lysis was independent of its ability to form hyphae. Taken together, our observations indicate that the physical formation of hyphae is not sufficient to trigger IL-1 beta secretion or macrophage lysis and suggest that other mechanisms, such as pyroptosis, a caspase-1-dependent response to intracellular pathogens, may play a role in the interaction of macrophages with C. albicans. IMPORTANCE The ability of Candida albicans to transition from yeast to filamentous cells plays an important and complex role in pathogenesis. Recent results from a number of investigators indicate that the host responds to yeast and hyphal C. albicans differently. For example, a C. albicans mutant unable to form hyphae also fails to induce interleukin 1 beta (IL-1 beta) secretion from macrophages. We have identified C. albicans transcription factor mutants that have decreased IL-1 beta secretion but retain the ability to form hyphae in response to macrophages. In addition, these mutants cause significantly less macrophage lysis. These observations indicate that the physical presence of the hyphal structure in the macrophage is not sufficient to trigger IL-1 beta secretion nor does it cause physical lysis of the cell. Our data indicate that characteristics of hyphae separate from its physical morphology are responsible for triggering the release of IL-1 beta release and causing macrophage lysis. Since these observations are inconsistent with some current models, alternative mechanisms for the interaction of C. albicans with macrophages must be considered.