Global
outbreaks caused by fluconazole-resistant (FLCR) C. parapsilosis
isolates impose an imminent threat to public health due to being associated
with higher mortality rates and outbreak persistence despite the application of
strict infection control strategies. Therefore, deeper clinical and
microbiological attributes associated with such outbreaks are warranted to
effectively combat this persistent global threat.
Through
acquisition of clinical C. parapsilosis isolates collected from
different countries and leveraging functional genetic analysis and extensive
models, this thesis aims at dissection of molecular pathways underpinning
antifungal resistance/tolerance and virulence. The expert review outlines the current
understanding regarding clinical, microbiological, and immunological attributes
associated with FLCR C. parapsilosis outbreaks. Whereas the other
chapters utilize genotyping tools, functional genetic studies and gene
expression analysis to understand the molecular mechanisms underpinning
antifungal resistance and tolerance. Through combination of whole-genome
sequencing (WGS) and diverse in-vitro, ex-vivo, and in-vivo analysis, we noted
that multidrug-resistant (MDR) C. parapsilosis isolates causing
outbreaks in Turkey exhibit robust fitness in various organs of immunocompetent
mice, which highlights the recent outbreaks caused by MDR C. parapsilosis
isolates as the next clinical threat. Finally, using state-of-the-art cell wall
analysis, WGS, extensive transcriptomics, phenotypic, ex-vivo, and in-vivo
systemic infection mouse models, we identify a cell wall remodeling underlying
tolerance to an antifungal drug and to critical components of innate immune
cells. Collectively, this thesis uncovers novel microbiological attributes
underlying antifungal resistance/tolerance and virulence and highlights unmet
need for future research to minimize the imminent threat posed by C.
parapsilosis in clinical settings.
