Abstract
Fungal infections, despite their substantial human health burden and clinical importance, remain relatively under-appreciated. The most common fungi in humans are the Candida species. These fungi are responsible for both superficial and life-threatening systemic infections in humans, with being the most common. C. albicans is found in the normal gastrointestinal, vaginal, and oral mucosal flora of healthy individuals.Changes in the host environment or immune response provide a cue for overgrowth and opportunistic pathogenic behaviour of C. albicans and lead to superficial infections such as oral and vaginal thrush. Despite potentially having a high morbidity, these infections are rarely lethal but may give rise to further disseminated or systemic infection. Given the high mortality rate of invasive infections in immunocompromised patients, a better understanding of host- Candida interactions is crucial. While many studies have focussed on immune cell interactions during systemic infection, there have been few studies investigating epithelial cell-Candida interactions during superficial infection.
In recent years, the importance of how metabolic pathways coordinate and/or impact on immune responses during infection has emerged as an important field in immunology. Numerous studies demonstrate the upregulation of glucose uptake and metabolism through aerobic glycolysis under normoxic conditions, along with disruption/suppression of the tricarboxylic acid (TCA) cycle in immune cells in response to microbial components. There is also early evidence to suggest that similar events occur in epithelial cells in response to bacteria. However, our current knowledge of the role of immunometabolism in infected epithelial cells is rudimentary. Given the importance of oral epithelial cells (OECs) as the primary site of interaction with C. albicans and its pivotal role in coordinating immunity to the fungus, this study investigated metabolic reprogramming of OECs induced by C. albicans. This study showed for the first time the modulation of class I glucose transporters (GLUT) expression in OECs after infection with both albicans and non-albicans Candida species (C. tropicalis, C. auris, C. glabrata). More specifically, the upregulation of GLUT14 in OECs was uniquely induced by C. albicans, suggesting GLUT14 might serve as a potential biomarker in oral candidosis. C. albicans exposure also committed OECs to upregulate aerobic glycolysis, as indicated by increases in glycolytic enzyme expression, lactate production, extracellular acidification rate, and ATP production. The importance of changes in glucose metabolism during infection was shown in a murine model of oropharyngeal candidosis, where inhibition of glycolysis resulted in decreased disease severity, whilst boosting glycolysis with glucose supplementation increased severity of the infection.
Since glucose metabolism is a highly complex series of multiple interconnected pathways, the complete metabolism of glucose-derived pyruvate was evaluated. This study showed that during C. albicans infection, OECs upregulate pyruvate carboxylase to generate oxaloacetate which feeds into a non-canonical glutamic-oxaloacetic transaminase-1 (GOT1) mediated pathway in addition to fermentation to lactate. Further, decreases in TCA cycle metabolites such as citrate suggests the repression of this cycle in OECs infected with C. albicans.
Hence, this study demonstrated the induction of aerobic glycolysis in OECs infected with C. albicans and provided preliminary data to suggest an additional pyruvate processing mechanism. Overall, this study provided fundamental insights into metabolic events and strategies induced by C. albicans in OECs that are crucial in mediating competent responses to this pathogen. These metabolic pathways may serve as emerging novel therapeutic targets for mucosal C. albicans infection.
| Date of Award | 1 May 2023 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Selvam Thavaraj (Supervisor), Dave Moyes (Supervisor) & Gordon Proctor (Supervisor) |