Characterizing The Regulation of Candida Albicans Hyphal Morphogenesis In The Context of Host Macrophages

<p><em>Candida albicans</em> is a commensal fungus that resides on the skin, mucosal surfaces, and in the gut of an estimated 80% of individuals. Though generally harmless, <em>C. albicans</em> is capable of causing uncomfortable mucosal infections as well as deadly disseminated infections depending on the immune status of the host. Although antifungal therapeutics exist, the mortality rate associated with disseminated disease still lingers around 50%. Further, <em>C. albicans</em> is the fourth most common cause of all bloodstream infections and continues to present as a major clinical issue with less than satisfactory treatment options. For this reason, it is imperative to understand the molecular mechanisms by which <em>C. albicans</em> shifts from commensal organism to deadly bloodstream pathogen in order to identify novel therapeutics.</p> <p>Innate immune cells are the first line of defense against <em>C. albicans</em>, and a fully functioning innate immune system confines <em>C. albicans</em> to commensal niches. Macrophages are sentinel cells equipped with the ability to engulf and exterminate invading pathogens while simultaneously activating and recruiting other immune effectors. However, <em>C. albicans</em> is able to adapt to the hostile environment of the macrophage phagosome, and in many cases, escape and kill the immune cell by undergoing hyphal morphogenesis.</p> <p>The Lorenz laboratory and others in the field have sought to understand the molecular underpinnings that define this dramatic interaction between fungus and immune cell. Although many aspects have been elucidated, including the transcriptional responses of the macrophage and the fungus, many questions remain. Specifically, it is currently unclear what triggers the morphological transition that allows <em>C. albicans</em> to escape the macrophage. The current models attempting to explain this process are conflicting and based on limited data.</p> <p>The purpose of my thesis research was to rigorously test specific molecular signals to determine their relevance in controlling the morphological switch after <em>C. albicans</em> is phagocytosed by a macrophage. These experiments were accomplished by disrupting pathways that allow <em>C. albicans</em> to form hyphae in response to hyphal-inducing stimuli (namely, pH and CO2) and determining if hyphal phenotypes were altered. Through my work, I have shown that both of these signals are dispensable for facilitating the morphological switch inside of macrophage phagosomes. Beyond testing these proposed signals, I also re-visited previous work showing that intracellular pH and hyphal morphogenesis are correlated. Using more robust approaches, I demonstrated that the intracellular pH of C. albicans is controlled tightly near neutral during morphogenesis, both <em>in vitro</em> and within macrophages, contrary to what was reported previously.</p> <p>Lastly, my thesis work sought to clarify data concerning the impact of extracellular pH on hyphal morphogenesis. Here, I’ve clearly demonstrated that extracellular pH does not directly suppress or promote morphogenesis. Rather, extracellular pH changes can impact the chemical composition of growth media as well as a variety of cellular processes. Together, these elements likely have a complex, indirect effect on the morphological state of <em>C. albicans</em>. My data show that morphological differences in response to pH changes are highly strain-dependent as well as medium-dependent. Altogether, these results argue that the regulation of hyphal morphogenesis is more complex than the current literature suggests, particularly in the context of host interactions.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2023

Authors dc:creator

• Wilson, Hannah
• <p>https://orcid.org/0000-0002-5466-6890</p>

Contributors dc:contributor

• Michael Lorenz, PhD
• Theresa Koehler, PhD
• Anna Konovalova, PhD

• Candida
• albicans
• pH
• CO2
• macrophages
• hyphae
• morphogenesis
• Immunology of Infectious Disease
• Microbial Physiology
• Molecular Genetics
• Pathogenic Microbiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1306

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2363