Results represent the average of two independent experiments each carried out with three mice per group. of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen. == INTRODUCTION == Changes in medical care are creating increasing opportunities for lethal systemic infections by Ibodutant (MEN 15596) the human fungal pathogenCandida albicans(1,2). In recent years,C. albicanshas become the fourth leading cause of hospital-acquired bloodstream infections, with close to 50,000 cases being reported yearly in the United States alone, and global mortality rates have not decreased in the last 20 years, in spite of advances in antifungal therapy (24). One underlying reason is usually thatC. albicansordinarily inhabits the skin and mucosa as a benign commensal. New medical procedures, such as malignancy chemotherapy or organ transplantation, that reduce host immunity allowC. albicansto escape normal physiological barriers and disseminate to deeper tissues. In addition, factors that permit the overgrowth ofC. albicans, including the use of broad-spectrum antibacterial antibiotics or biofilm formation on catheters and indwelling medical devices, allow this fungus to infect immunocompetent individuals (5). Better antifungal therapies are needed to address this escalating problem (6). During the course of contamination, kidneys are highly favorable niches for both fungal proliferation and the morphogenetic switch ofC. albicansto a hyphal state (7,8). Recent analysis has drawn attention to the intensity of the immune response following systemic contamination. On the one hand, the innate immune system that is critical for host protection is rapidly activated. In particular, fungal cell wall constituents are recognized by Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) on the surface of phagocytes within the kidney, promoting the release of Ibodutant (MEN 15596) cytokines and chemokines that lead to the infiltration of additional waves of monocytes and neutrophils into the kidney (9,10). On the other hand, it has become appreciated that host inflammatory responses targetingC. albicanslead to detrimental and often fatal collateral tissue damage (11). Indeed, in Ibodutant (MEN 15596) a well-characterized mouse model of systemic candidiasis that mimics the clinical progression of disseminated candidiasis in humans, progressive sepsis accompanied by renal failure has been identified as the cause of death (12). Thus, destructive inflammatory responses leading to pathological tissue destruction is a significant clinical problem. Current antifungal medications suffer from a number of drawbacks, including high cost, toxicity, and a narrow spectrum of activity (13). These limitations are compounded by troubles in making a rapid and accurate disease diagnosis (14). The emergence of strains resistant Rabbit Polyclonal to FOXC1/2 both to fluconazole and to newer members of the echinocandin class of compounds is now considered a major threat by the CDC (15). Because no effectiveC. albicansvaccine is currently available, developing strategies for enhancing host immune responses that synergize with current medications holds great promise (16). Indeed, attempts to develop combination therapies, such as the coadministration of antifungal monoclonal antibodies or adjuvant immunotherapy with recombinant cytokines to boost a patient’s immune response, are ongoing (1719). The development of combination therapies that are most effective will require a thorough understanding of the host antifungal immune response. To gain new insight into the mechanisms that control the host response to fungal pathogens, we examined the role of thesuppressor ofTCRsignaling 1 (Sts-1) and Sts-2, two homologous proteins that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets (2023). These evolutionarily conserved proteins share 50% amino acid identity and appear to carry out overlapping functions. However, their expression patterns differ markedly, in thatSts-1has been found to have a.