Author ORCID Identifier

https://orcid.org/0000-0003-4745-9276

Date of Graduation

12-2018

Document Type

Dissertation (PhD)

Program Affiliation

Microbiology and Molecular Genetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michael Lorenz, Ph.D.

Committee Member

Theresa Koehler, Ph.D.

Committee Member

Kevin Morano, Ph.D.

Committee Member

Nayun Kim, Ph.D.

Committee Member

Shane Cunha, Ph.D.

Abstract

Candida albicans is the most important fungal species associated with humans. Normally present in the human microbiome as a commensal colonizer, C. albicans is also the fourth most prevalent organism isolated from bloodstream infections in hospitals. Disseminated infections have an associated mortality rate of around 40%. The results of the work described in this dissertation cover the broad subject of C. albicans adaptation to the host and the mechanisms by which this organism is able to survive and cause infection through a variety of means. A key determinant in disease progression is interaction with innate immune cells, specifically macrophages and neutrophils. Due to the few options of current antifungal drugs and rising rates of drug resistance, building our understanding of C. albicans pathogenicity is key to determining how this fungal species interacts with the cells most responsible for its recognition and clearance. Alternative carbon utilization has been shown throughout the years to be an essential requirement for C. albicans in host-pathogen interaction models. This idea is expanded in this thesis by the discovery of additional genetic contributors to pH neutralization, a process that is critical for survival after phagocytosis by macrophages, and that the utilization of amino acids and N-acetylglucosamine are genetically distinct pathways. Furthermore, there are uncharacterized genes that C. albicans upregulates upon contact with mammalian macrophages and these genes are involved in well-described virulence mechanisms. The majority of these newly annotated genes were completely unstudied at the outset of this study and I have described the first in vitro and in vivo phenotypic assessments of several of these. Mia1, a microadhesin that has virulence-associated phenotypes is characterized for the first time in this study. We hypothesize that this small adhesin may serve a broader role of coordinating other surface adhesins based on the data presented. Taken together, this work describes new contributors to pathways known to affect the interactions of C. albicans with the host, which may inform future guided efforts to therapeutically target the virulence of C. albicans.

Keywords

Fungal pathogenesis, Candida albicans, pH neutralization, small proteins

Available for download on Friday, December 13, 2019

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