The overarching goal of Khoshnevis laboratory, within the Department of Biochemistry at Emory University, is to define the molecular mechanisms of post-transcriptional regulation of the virulence in the human fungal pathogen Candida albicans. C. albicans is a prevalent human fungal pathogen, a leading cause of nosocomial infection, and the cause of an estimated 700,000 severe cases of candidiasis per year with a mortality rate of 40%. C. albicans is a commensal organism found in the gastrointestinal tract, mouth, skin, and female reproductive tract that can cause superficial mucosal infection. These infections can be life-threatening in immunocompromised patients, including organ transplant recipients, cancer and HIV/AIDS patients. The current treatments are mostly restricted to polyenes, azoles, and echinocandins. The use of these antifungals is limited by toxicity, drug-drug interactions, and the emergence of resistance, underscoring the importance of identifying novel therapeutic targets and the need for new treatment approaches.
C. albicans can undergo a morphological transition from single oval cells (yeast) to elongated cells (hyphae); this process is important for its pathogenicity. Understanding the molecular basis for yeast-to-hyphae transition is, therefore, of great importance to find new ways to combat Candida infections. A long-term goal of our laboratory is to identify the post-transcriptional mechanisms that regulate protein synthesis and understand their contribution to fungal pathogenicity. We focus on two areas of post-transcriptional gene regulation: mRNA modifications and translational control. These two areas represent a significant gap in our knowledge of how these processes can rapidly affect cellular plasticity in response to the changes in environmental cues in C. albicans.
Translational control of cell-type switching in C. albicans: One of the main goals of our research is to address the role of translation machinery in controlling cell plasticity in C. albicans. Our efforts are currently focused on two translation factors: eIF3 and eEF3. The eukaryotic translation initiation factor 3 (eIF3) has emerged as a master player in translation regulation by promoting or suppressing the translation of a subset of mRNAs. However, how this key initiation factor controls cell plasticity is not understood. Similarly, the eukaryotic translation elongation factor 3 (eEF3), an AAA-ATPase that is fungal-specific, is important in pathogenesis but its role in cell plasticity remains unknown. Through a combination of biochemical, structural, and cell-based approaches we aim to characterize the role of eEF3 in morphological transition in C. albicans and target it to design new classes of antifungals.
The role of post-transcriptional modifications in the pathogenicity of C. albicans: A second area of research in our lab is focused on understanding how RNA modifications regulate cell plasticity in C. albicans. By combining novel genetic tools and reagents that we have developed with biochemical assays, proteomics, and next-generation sequencing we aim to answer two key questions: 1) What is the mechanism of m6A deposition on mRNAs during cell-type switching in C. albicans? and 2) How do RNA modifications contribute to cell-type switching and pathogenicity in C. albicans? By answering these questions, we hope to provide significant insights into the mechanisms of post-transcriptional control of cell plasticity in C. albicans that will aid in understanding how dysregulation of these processes contributes to pathogenicity.