Candida species are the most important fungal pathogens of humans, and Candida albicans, in particular, is the most common cause of oropharyngeal candidiasis, which is an infection that affects patients suffering from Acquired Immune Deficiency Syndrome (AIDS) among other ailments. Candida are also the fourth most common cause of systemic infections (~30% mortality rate) in intensive care units This fellowship proposal explores the hypothesis that the phospholipids phosphatidylethanolamine (PE) and phosphatidylserine (PS) affect virulence by affecting signal transduction pathways that regulate virulence factors necessary for adhering to and invading host tissues, as well as evasion of the host's immune response. Little is known about the how phospholipid synthesis pathways regulate disease, but some of these pathways differ from those in mammals and may provide new drug targets. Two different pathways synthesize PE in C. albicans. The de novo pathway synthesizes PE from PS, which itself is synthesized by only one enzyme, Cho1p. In addition, the Kennedy pathway makes PE from extracellular ethanolamine. Mutants completely blocked in de novo PS and/or PE synthesis (cho1?/? and psd1?/? psd2?/?, respectively) are avirulent, have a significant drop in PE, expose cell wall ?-glucans (an immune marker for fungal infections) to enhanced detection by the immune system, and adhere to invade host epithelial cells poorly. In addition, these mutants are ethanolamine auxotrophs, and it is possible that the mutants suffer a fitness defect in the host due to insufficient ethanolamine supplies. It s hypothesized that mutations that completely block the de novo PE synthesis pathway affect virulence by compromising cell signaling cascades within the cell, resulting in drastic changes in presentation of cell surface proteins involved in host adherence and immune evasion. These changes in PE synthesis may also decrease fitness of C. albicans in the host due to ethanolamine auxotrophy. This hypothesis will be tested in three aims: 1) Observe differences in cell signaling pathways known to be involved in the regulation of virulence and adherence to host tissues (ie. Rim101 pathway), 2) Determine if PS and PE play a role in evading the immune response 3) Discover if auxotrophy for ethanolamine, a known substrate of PE, affects virulence of the mutants in the host.
Candida albicans is among the most important fungal pathogens of humans and causes oral infections in a variety of patients including neonates, the elderly, patients taking corticosteroids or antibiotics, denture wearers and AIDS patients, as well systemic infections in intensive care unit patients with high mortality rates (30%). One of the pathways for generating the phospholipids phosphatidylethanolamine (PE) and phosphatidylserine (PS) regulates virulence in this fungus by affecting both offensive and defensive virulence factors. An understanding of how this pathway regulates virulence will provide information that will help us better understand its mechanisms for causing disease and could lead to novel drug targets.
|Davis, Sarah E; Hopke, Alex; Minkin Jr, Steven C et al. (2014) Masking of Î²(1-3)-glucan in the cell wall of Candida albicans from detection by innate immune cells depends on phosphatidylserine. Infect Immun 82:4405-13|