In recent years, the human fungal pathogen Candida albicans has become the fourth leading cause of hospital-acquired bloodstream infections, with close to 50,000 cases reported yearly in the United States. The number of yearly deaths in the U.S. due to systemic C. albicans infection now exceeds the number of deaths due to HIV. In a mouse model of systemic candidiasis that mimics disseminated candidiasis in humans, progressive sepsis accompanied by renal failure was identified as the cause of death.

Our collaborator, Dr. Nick Carpino, recently evaluated mice lacking the proteins Sts-1 and Sts-2 for susceptibility to systemic C. albicans infection. In striking contrast to wild-type mice, which succumb to pyelonephritis within days of infection, Sts-/- mice were profoundly resistant to infection. The Sts-null phenotype was associated with enhanced pathogen clearance, sharply diminished levels of many inflammatory  molecules beginning at 24 hours post infection, a reduction in kidney leukocyte infiltrates, and an absence of inflammatory lesions.

The Sts proteins are characterized by a distinctive C-terminal histidine phosphatase domain, making them structurally and enzymatically very distinct from other phosphatases. Their singular enzymatic properties suggest they are attractive therapeutic targets. We are working with the Carpino lab to characterize the structures of the human Sts proteins, to optimize assays for inhibitor screening and to identify novel inhibitors as leads for further drug development. The long-term success of this work has the potential to significantly reduce the morbidity and mortality attributed to systemic Candida infections.

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Structural and functional characterization of the histidine phosphatase domains of human Sts-1 and Sts-2. Zhou W, Yin Y, Weinheimer AS, Kaur N, Carpino N, French JB. Biochemistry. 2017 Jul 31. doi: 10.1021/acs.biochem.7b00638. [Epub ahead of print]