Date of Award

Summer 8-16-2024

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Robert T. Wheeler

Second Committee Member

Melody N. Neely

Third Committee Member

Melissa Maginnis

Additional Committee Members

Josh Kelley

James A. Coffman

Abstract

Candida is one of the most frequent causes of bloodstream infections in the U.S. The first line of defense against these invasive infections is the innate immune system. Previous work suggests that early immune response is critical in controlling C. albicans infection, but C. albicans has several strategies to evade the host immune system. Evidence suggests that the ability to transition from yeast to hyphal growth may facilitate immune evasion by limiting early phagocyte recruitment and uptake of Candida albicans. Reduced containment of C. albicans can lead to uncontrolled hyphal growth, causing damage that can lead to death. However, the mechanism by which C. albicans limits recruitment or containment is unknown. To uncover factors important in innate immune evasion, we utilized the transparent larval zebrafish infection model to screen 131 C. albicans mutants for altered virulence and immune response. Several mutants with reduced virulence also induced an altered immune response. NMD5 was found to play a role in limiting phagocytosis, while BRG1 and PEP8 were found to modulate the recruitment of macrophages and or neutrophils to the infection site.

Host cells interact with microbial cell wall proteins and secreted products. RBT1 codes for a hyphal cell wall protein that also contains two secreted peptides, but little is known about its role in pathogenesis. Our preliminary studies suggest that Rbt1p-derived peptides may play a role in virulence. C. albicans also has a family of secreted lipases and little is known about how they contribute to virulence. We found that a lipase deficient mutant had reduced virulence. LIP8 also appears to be important for virulence, but overexpression of this gene could not compensate for the loss of the other lipases.

These results begin to elucidate how lipases and other genes drive virulence. They also identify three new regulators of Candida-phagocyte interaction and distinguish recruitment from containment, suggesting that Candida modulates both events. This work highlights the ability of C. albicans to use multiple strategies that regulate different steps of the immune response such as recruitment and uptake.

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