Gastrointestinal colonization by Candida albicans modulates host defence in sepsis

Changirwa, Diana Kasoha

Gastrointestinal colonization by Candida albicans modulates host defence in sepsis

dc.contributor.advisor	McDonald, Braedon
dc.contributor.author	Changirwa, Diana Kasoha
dc.contributor.committeemember	Arrieta, Marie Claire
dc.contributor.committeemember	Mody, Christopher
dc.date.accessioned	2024-05-08T16:21:30Z
dc.date.available	2024-05-08T16:21:30Z
dc.date.issued	2024-05-07
dc.description.abstract	Pathological dysbiosis of the intestinal microbiome can lead to defects in immune homeostasis and a breakdown in host defense that increases susceptibility to infection. This is particularly relevant in patients with sepsis, a disorder of infection-induced systemic immune dysregulation and multi-organ dysfunction, where dysbiosis of the bacterial microbiome in these patients has been associated with adverse clinical outcomes. However, the impact of the fungal microbiome on sepsis pathogenesis has not been characterized. Analysis of the gut fungal microbiome in critically ill patients with sepsis identified severe fungal dysbiosis driven by marked overgrowth of Candida. Based on these clinical observations, we sought to investigate the functional impact of intestinal Candida overgrowth on systemic inflammation and host defense using mouse models. We colonized the gastrointestinal tracts of antibiotic-conditioned SPF C57BL/6 mice with different strains of C. albicans (including hyphal and yeast morphotypes) for 10 days prior to infection/sepsis with a well-characterized model of S. aureus bloodstream infection. The data indicated that colonizing mice with a yeast-locked strain of C. albicans displayed reduced illness severity, reduced systemic inflammation, and enhanced protection against systemic pathogen dissemination compared to uncolonized mice. In contrast, mice colonized with hyphal/filamentous C. albicans displayed similar illness severity, systemic inflammation, and pathogen burden as uncolonized controls. Further analysis of the immune landscape with mass cytometry indicated that yeast colonized mice have increased liver neutrophils. To test the therapeutic applicability of these findings, we treated hyphal colonized with yeast C. albicans to determine if it could displace hyphal C. albicans and impart immunological benefits. We found that yeast-treated mice had hyphal C. albicans physically displaced from their gut compartment by yeast treatment, and these treated mice had reductions in systemic pathogen burden. To expand upon this, we determined that genetically yeast locked strains (flo8-/-) are also able to displace wild-type C. albicans (SC5314), suggesting that these findings are likely applicable to a diverse amount of yeast-locked strains. Together, this project determined the impact of C. albicans gut colonization on the systemic host response, while describing immune mechanisms mediating this response and identifying the therapeutic potential of treatment with yeast C. albicans.
dc.identifier.citation	Changirwa, D. K. (2024). Gastrointestinal colonization by Candida albicans modulates host defence in sepsis (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/118718
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	Microbiota
dc.subject	Sepsis
dc.subject	Candida albicans
dc.subject	Systemic infection
dc.subject	Intravascular immunity
dc.subject	Mycobiome
dc.subject.classification	Immunology
dc.title	Gastrointestinal colonization by Candida albicans modulates host defence in sepsis
dc.type	master thesis
thesis.degree.discipline	Medicine – Immunology
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.