Background: Our laboratory has demonstrated that lethal gut-derived sepsis in mice due to P. aeruginosa is dependent on the local concentration of phosphate owing to the presence of a highly conserved phosphoregulatory system in this pathogen that detects low phosphate and activates its quorum sensing signaling system. Here we determined if this conserved mechanism of virulence activation can also be demonstrated for the opportunistic fungal pathogen C. albicans which is also known to be a common cause of lethal gut-derived sepsis.

Methods: Hyphae formation, an inducible morphological change known to shift C. albicans to an invasive and virulent phenotype, was assessed using a strain of C. albicans isolated from the stool of a critically ill patient. The strain was examined under phosphate [Pi] limiting conditions using a SZX16 Olympus stereomicroscope. To determine if C. albicans can kill its host when exposed to low phosphate conditions, we injected C. albicans (107 CFU) into the mouse cecum following a 30% hepatectomy, a known model of local intestinal phosphate depletion as well as into similarly operated mice orally replenished of Pi (25mM). Adhesiveness of C. albicans in intestinal tissues from mice was examined between groups by scanning electron microscope (SEM) using a FEI Nova NanoSEM 200 (FEI, USA).

Results: C. albicans grown on agarized media depleted of phosphate was observed to shift to its hyphae-like form (see Figure), a phenotype associated with invasion and dissemination. Mice undergoing 30% and intestinal inoculation of C. alb cans had a mortality rate of 66.6% at 48 hours (n=9, p<0.03) whereas mortality in this model decreased to 33.3% (n=9) when the intestinal tract was phosphate repleted with oral phosphate supplementation. Examination of intestinal tissues by SEM revealed evidence of abundant hyphae among C. albicans present in the phosphate depleted environment of the mouse cecum following 30% hepatectomy with evidence of loss of the normal epithelial architecture. However mice orally supplemented with Pi demonstrated suppression (absence) of hyphae formation among identified C. albicans and preservation of normal intestinal architecture.

Conclusion: These data show for the first time that C. albicans-mediated lethal gut- derived sepsis can be experimentally modeled to occur following surgical injury alone, without pharmacologic immunosuppression and without antibiotic decontamination of the normal flora. In addition we show that C. albicans shifts its morphology in response to surgical injury in a phosphate dependent manner. Taken together, results of this study suggest that maintenance of local phosphate sufficiency may be a novel approach to prevent gut- derived dissemination/sepsis from C. albicans and merits further study.