Candida albicans is the most prevalent human fungal pathogen and is an important cause of morbidity and mortality in patients with compromised immune function. Life-threatening, invasive C. albicans infections generally affect immunocompromised people, while superficial infections of the urogenital and oral mucosa also cause significant morbidity in immunocompetent individuals. Consequently, the mechanisms by which the immune system maintains C. albicans as a commensal organism and limits infections to superficial mucosa are central to understanding C. albicans pathogenesis. A crucial aspect of the host response to C. albicans involves the interaction of the fungus with macrophages. Macrophages are key regulators of local immune homeostasis which perform both effector and signaling functions in response to fungi. The interaction of C. albicans with macrophages leads to varying degrees of damage to both cells as well as IL-1 production. This process was most commonly attributed to the ability of C. albicans to form filamentous hyphal within the macrophage. We have recently found that hypha formation is not sufficient for either process. We have shown further that a programmed cell death pathway called pyroptosis may play a role in this interaction. The molecular mechanism by which C. albicans activates pyroptosis is unknown. We have found that filamentous strains of the model yeast S. cerevisiae also activate pyroptosis. In this application, we propose to exploit this finding as a means to use a genome-wide screening approach to identify genes that modulate yeast-mediated macrophage pyroptosis.
The specific aims of the application are: 1) identify S. cerevisiae genes that modulate macrophage NLRP3 inflammasome activation and 2) determine the effect of candidate yeast triggers of NLRP3-mediated pyroptosis in C. albicans.
Candida albicans is the most common human fungal pathogen. Although it can cause superficial mucosal infections in immunocompetent patients, it is biggest impact is as an opportunistic pathogen that causes significant morbidity and mortality among patients with compromised immune function. For example, nearly all HIV-infected individuals will develop either oral pharyngeal (OPC) or esophageal candidiasis (EC) at some point in their lives. The interaction of C. albicans with the host immune system is an important part of its mechanism of disease. The goal of the research proposed in this application is to identify yeast genes that mediate the interaction of C. albicans with phagocytes, key players in the host response to C. albicans infection and which participate in eliminating the pathogen and signaling to other components of the immune response. Understanding this interaction will allow physicians to better identify the factors that put patients at risk for these infections and could lead to better approaches to treatment.
| Phadke, Sujal S; Maclean, Calum J; Zhao, Serena Y et al. (2018) Genome-Wide Screen for Saccharomyces cerevisiae Genes Contributing to Opportunistic Pathogenicity in an Invertebrate Model Host. G3 (Bethesda) 8:63-78 |
| O'Meara, Teresa R; Duah, Kwamaa; Guo, Cynthia X et al. (2018) High-Throughput Screening Identifies Genes Required for Candida albicans Induction of Macrophage Pyroptosis. MBio 9: |
| Chang, Ya-Lin; Yu, Shang-Jie; Heitman, Joseph et al. (2017) New facets of antifungal therapy. Virulence 8:222-236 |
