Date of Award

Summer 8-19-2016

Level of Access

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology

Advisor

Robert Wheeler

Second Committee Member

Carol Kim

Third Committee Member

Derry Roopenian

Additional Committee Members

Julie Gosse

John Singer

Abstract

Molecular camouflage is used by a diverse set of pathogens to disguise their identity and avoid recognition by protective host receptors. The opportunistic fungal pathogen Candida albicans is a good example, as it masks the inflammatory component β-glucan in its cell wall to evade detection by the immune receptor Dectin-1. Interestingly, it has been seen that β-glucan becomes unmasked during infection in vivo, though the underlying mechanisms remained unclear. Exposure levels of this epitope may be important, as Dectin-1 mediates protection from some strains of C. albicans and alterations in the organization and composition of the Candida cell wall can influence host responses.

This research sought to understand C. albicans cell wall dynamics, particularly within the context of host-pathogen interactions. Special attention was paid to elucidating mechanisms of β-glucan unmasking and we have revealed a novel and dynamic interaction in which neutrophils damage the fungal cell wall via a mechanism involving neutrophil extracellular traps. This damage provoked the disruption of fungal cell wall architecture including increased chitin deposition and β-glucan unmasking at sites of immune attack. Surprisingly, these cell wall changes were also dependent on an active fungal response, which required cell wall integrity signaling and involved relocalization of cell wall remodeling components. Importantly, neutrophil mediated β-glucan unmasking could result in enhanced immune responses to fungi from macrophages, suggesting that this epitope unmasking could have functional consequences during infection. Work we participated in helped elucidate mechanisms involved in baseline fungal epitope masking in the form of Cho1 and phosphatidylserine biosynthesis and also demonstrated that changes to cell wall composition and architecture influence the importance of β-glucan exposure to host responses to C. albicans.

Overall, this work helps elucidate the importance of host-pathogen interactions in influencing fungal cell wall dynamics during disseminated candidiasis. Given the importance of the cell wall as a drug target, understanding how this fungus maintains integrity and epitope masking during attack may identify therapeutic targets to aid the treatment of candidiasis. This work also highlights an important concept, which is that microbial cell walls can change dynamically during infection with important consequences for host recognition and immunity.

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