Mucosal Infection with Unmasked Candida albicans Cells Impacts Disease Progression in a Host Niche-Specific Manner

Shielding the immunogenic cell wall epitope beta(1, 3)-glucan under an outer layer of mannosylated glycoproteins is an essential virulence factor deployed by Candida albicans during systemic infection. Accordingly, mutants with increased beta(1, 3)-glucan exposure (unmasking) display increased immunostimulatory capabilities in vitro and attenuated virulence during systemic infection in mice. However, little work has been done to assess the impact of increased unmasking during the two most common manifestations of candidiasis, namely, oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC). We have shown previously that the expression of a single hyperactive allele of the MAP3K STE11(Delta N467) induces unmasking via the Cek1 MAPK pathway, attenuates fungal burden, and prolongs survival during systemic infection in mice. Here, we expand on these findings and show that infection with an unmasked STE11(Delta N467) mutant also impacts disease progression during OPC and VVC murine infection models. Male mice sublingually infected with the STE11(Delta N467) mutant showed a significant reduction in tongue fungal burden at 2 days postinfection and a modest reduction at 5 days postinfection. However, we find that selection for STE11(Delta N467) suppressor mutants that no longer display increased unmasking occurs within the oral cavity and is likely responsible for the restoration of fungal burden trends to wild-type levels later in the infection. In the VVC infection model, no attenuation in fungal burden was observed. However, polymorphonuclear cell recruitment and interleukin-1 beta (IL-1 beta) levels within the vaginal lumen, markers of immunopathogenesis, were increased in mice infected with unmasked STE11(Delta N467) cells. Thus, our data suggest a niche-specific impact for unmasking on disease progression.

Automated summary

This study investigates the impact of beta(1, 3)-glucan unmasking on the progression of two manifestations of candidiasis: oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC). The results show that increased unmasking attenuates fungal burden and prolongs survival in systemic infection. However, in OPC, selection for suppressor mutants that no longer display increased unmasking occurs, leading to restoration of fungal burden trends. In VVC, unmasked cells increase recruitment of polymorphonuclear cells and interleukin-1beta levels within the vaginal lumen. These findings suggest a niche-specific impact of unmasking on disease progression.