Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases

Abstract

The human fungal pathogen Candida albicans causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. The suppressor of TCR signaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection by C. albicans, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose of C. albicans (2.5 ؋ 10 5 CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction 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.

Structural and Functional Characterization of the Histidine Phosphatase Domains of Human Sts-1 and Sts-2

“…Knockout of the Sts proteins in mice confers a profound resistance to fungal infection without deleterious immunopathology 11 . This highlights the clinical relevance of the Sts proteins as potential immuno-modulatory targets for the treatment of deadly pathogen infections.…”

“…A comparison of the MmSts-1 HP to MmSts-2 HP showed a high degree of structural similarity, yet some notable structural differences in the active site 6, 12, 14 . Functional studies, both in vitro and in vivo , showed that Sts-1 has a much higher phosphatase activity than that of Sts-2, both on non-native substrates and the putative protein substrate, Zap-70 6, 11, 14, 17 . The mechanism of catalysis is believed to resemble that of other histidine phosphatases, proceeding through a covalent phosphor-histidine intermediate 8, 18–20 .…”

“…In a mouse model which mimics disseminated candidiasis in humans, mice were found to be profoundly resistant to infection without hyperinflammatory response that would cause tissue damage 11 . In addition, the mice lacking the Sts proteins were associated with a significant reduction in fungal burden 11 . This result underscores the role of the Sts proteins in regulating host responses to fungal pathogens and their potential as host-modulatory drug targets for antifungal therapies.…”

Specific Human and Candida Cellular Interactions Lead to Controlled or Persistent Infection Outcomes during Granuloma-Like Formation

“…Previous studies have shown that CD4 + T cells in mice are significantly produced after stimulation with Candida antigens (65). It has been proposed that specific protection against a variety of mycoses corresponds to the activation of CD4 + T cells (66). Other studies have suggested a role for CD8 + T cells in the elimination of C.…”

TULA‐family proteins: Jacks of many trades and then some

“…These studies allowed researchers to evaluate individual contributions of the two family members to the immune response. Thus, the protective host response to systemic Candida albicans infection as judged by an increase in survival was significantly enhanced not only in dKO mice, but also in mice lacking either family member (Naseem, Frank, Konopka, & Carpino, ). Although this study provides no direct evidence of the involvement of T cells in the observed enhancement of immunity, an increase in the host response to Candida albicans caused by the deficiency of only TULA, a lymphoid protein, suggests that T cells might play a role in facilitating immunity in this system.…”