Candida albicans is a frequent causative agent of oropharyngeal candidiasis (OPC), an infection of the oral mucosa. OPC causes significant morbidity among patients with diverse risk factors, including dentures, diabetes, cancer, HIV/AIDS, use of antibiotics or corticosteroids, dry mouth, and smoking. There is no surveillance for these infections in the US, but worldwide estimates indicate that HIV/AIDS patients alone present 10 million cases of OPC annually. Clinical practice guidelines recommend azole antifungal treatment for OPC. However, azole resistance continues to emerge, in particular after repeated exposure, and it is thus critical to develop new strategies to prevent and treat OPC. The C. albicans genes and pathways that govern pathogenicity in OPC have not been extensively characterized. Only 14 C. albicans genes are known to be required for virulence in the mouse model of OPC. We have used RNA-seq expression profiling of C. albicans in a mouse OPC infection model to identify candidate virulence determinants. Infecting C. albicans cells expressed high RNA levels for genes that enable alternative (i.e., non-glucose) carbon source utilization. This observation suggests that C. albicans cells proliferate on alternative carbon sources during OPC. We have found that two C. albicans transcription factors, Mig1 and Mig2, function redundantly to shut off alternative carbon utilization genes. Our data suggest that effects of Mig1 and Mig2 may be mediated in part by two transcriptional activators of alternative carbon utilization genes, Adr1 and Try4. Both ADR1 and TRY4 RNAs are greatly up-regulated in C. albicans cells in the OPC model, compared to cells grown in RPMI. These results led us to the hypothesis that Adr1 and Try4 are required to activate alternative carbon utilization genes in infecting C. albicans cells during OPC, enabling their proliferation and, ultimately, OPC pathogenesis. We seek to define functional relationships among alternative carbon utilization genes, their regulators, and OPC pathogenesis through definition of the regulatory circuitry that governs alternative carbon utilization genes downstream of Mig1 and Mig2, and through definition of the impact of defects in carbon utilization and its regulation on OPC. Carbon utilization has been studied in the context of invasive candidiasis and gut colonization. To our knowledge, though, there have been no functional studies of carbon utilization in OPC. The results of our analysis will uncover basic aspects of C. albicans biology during OPC. This information will likely be applicable to other mucosal infections, such as vulvovaginal candidiasis, and holds promise to identify novel targets for antifungal agents.

Public Health Relevance

Candida albicans is a frequent causative agent of oropharyngeal candidiasis (OPC). This infection causes significant morbidity among patients diverse risk factors that include dentures, diabetes, cancer, HIV/AIDS, use of antibiotics or corticosteroids, dry mouth, and smoking. Our studies seek to define new C. albicans genes that promote pathogenesis of OPC by enabling active metabolism in the oral environment.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Pathogenic Eukaryotes Study Section (PTHE)
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Love, Dona
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University of Georgia
Schools of Arts and Sciences
United States
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