Modulating Host Signaling Pathways to Promote Resistance to Infection by Candida albicans

Abstract

Candida albicans is a common human fungal pathogen capable of causing serious systemic infections that can progress to become lethal. Current therapeutic approaches have limited effectiveness, especially once a systemic infection is established, in part due to the lack of an effective immune response. Boosting the immune response to C. albicans has been the goal of immunotherapy, but it has to be done selectively to prevent deleterious hyperinflammation (sepsis). Although an efficient inflammatory response is necessary to fight infection, the typical response to C. albicans results in collateral damage to tissues thereby exacerbating the pathological effects of infection. For this reason, identifying specific ways of modulating the immune system holds promise for development of new improved therapeutic approaches. This review will focus on recent studies that provide insight using mutant strains of mice that are more resistant to bloodstream infection by C. albicans. These mice are deficient in signal transduction proteins including the Jnk1 MAP kinase, the Cbl-b E3 ubiquitin ligase, or the Sts phosphatases. Interestingly, the mutant mice display a different response to C. albicans that results in faster clearance of infection without hyper-inflammation and collateral damage. A common underlying theme between the resistant mouse strains is loss of negative regulatory proteins that are known to restrain activation of cell surface receptor-initiated signaling cascades. Understanding the cellular and molecular mechanisms that promote resistance to C. albicans in mice will help to identify new approaches for improving antifungal therapy.

Keywords: Candida albicans; Cbl-b; Jnk1; Sts-1; Sts-2.

Figure 1

Functional domains of Jnk1, Cbl-b, and Sts-1/2 proteins. Diagrams indicate the important functional domains and the length of the proteins. Abbreviations include TKB, Tyrosine Kinase Binding; RF, Ring Finger; UBA, Ubiquitin association; and SH3, Src homology-3.

Figure 2

Predicted functions of Jnk1, Cbl-b, and Sts-1/2 in cell signaling. Model for how loss of function of Jnk1, Cbl-b, or the Sts proteins promotes resistance to C. albicans. The right side shows a diagram of signaling pathways in phagocytic cells of the innate immune system. Jnk1 negatively regulates the NFATc1 transcription factor to suppress expression of Fcer2a (CD23). CD23 activation induces expression of Nos2 (iNOS). Cbl-b is an E3 ligase that regulates the ubiquitination of Dectin receptors (Dectin-1,−2,−3) and the Syk protein kinase, thereby regulating their levels of expression. In T cells Sts-1 and −2 are phosphatases that counteract the activation of the kinase Zap-70 downstream of TCR engagement (left side). Syk is a homolog of Zap-70 expressed in phagocytes, suggesting the Sts proteins could negatively regulate Syk activity.