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Host Adaptation at the Cost of Biofilm Formation Drives Outbreak Persistence of a Major Human Fungal Pathogen [macrophages]

ABSTRACT: Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by drug-resistant (DR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbiological traits underlying the persistence of these outbreak strains remain poorly understood. Here, we show that DR-Cp isolates responsible for prolonged outbreaks across multiple countries exhibit a striking low-biofilm-producing (LBP) phenotype. Unexpectedly, LBP strains display enhanced stress tolerance, cell wall masking, and immune evasion, leading to resistance against neutrophil and macrophage killing and increased survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains, while whole-genome sequencing (WGS) of a global isolate collection demonstrated that the LBP phenotype has arisen independently multiple times. Functional genetic analyses identified a previously uncharacterized transcription factor whose mutation markedly reduces biofilm formation but simultaneously enhances fitness during host immune interactions. Together, our findings challenge the prevailing view that robust biofilm formation underlies Candida outbreak persistence and instead reveal that host immune pressure selects for biofilm attenuation as an adaptive strategy promoting long-term persistence. These insights redefine how C. parapsilosis adapts during healthcare-associated outbreaks and inform infection control strategies by shifting attention toward non-environmental reservoirs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE344550 | GEO | 2026/08/20

REPOSITORIES: GEO

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Project description:Abstract: Candida parapsilosis and Candida albicans are human fungal pathogens that belong to the CUG clade in the Saccharomycotina. In contrast to C. albicans, relatively little is known about the virulence properties of C. parapsilosis, a pathogen particularly associated with infections of premature neonates. We describe here the construction of >200 C. parapsilosis strains carrying double allele deletions of transcription factors, protein kinases and species-specific genes. Two independent deletions were constructed for each target gene. Growth in > 40 conditions was tested, including carbon source, temperature, and the presence of antifungal drugs. The phenotypes were compared to C. albicans strains with deletions of orthologous transcription factors. We found that many phenotypes are shared between the two species, such as the role of Upc2 as a regulator of azole resistance. Others are unique. For example, Cph2 plays a role in the hypoxic response in C. parapsilosis and not in C. albicans. We found extensive divergence between the biofilm regulators of the two species. We identified 7 transcription factors and one protein kinase that are required for biofilm development in C. parapsilosis. Only three (Efg1, Bcr1, and Ace2) have similar effects on C. albicans biofilms, whereas Cph2, Czf1, Gzf3 and Ume6 have major roles in C. parapsilosis only. In addition, two transcription factors (Brg1 and Tec1) with well-characterized roles in biofilm formation in C. albicans do not have the same function in C. parapsilosis. We also compared the transcription profile of C. parapsilosis and C. albicans biofilms. Our analysis suggests the processes shared between the two species are predominantly metabolic. C. parapsilosis mRNA profiles of wild type (WT) at 37 degree celcius in planktonic growth conditions and ace2-/-, cph2-/-, efg1-/-, czf1-/-, ume6-/-, bcr1-/- and WT in biofilm conditions were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.

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Host Adaptation at the Cost of Biofilm Formation Drives Outbreak Persistence of a Major Human Fungal Pathogen [macrophages]

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