Investigation of Candida parapsilosis virulence regulatory factors during host-pathogen interaction

Abstract

Invasive candidiasis is among the most life-threatening infections in patients in intensive care units. Although Candida albicans is the leading cause of candidaemia, the incidence of Candida parapsilosis infections is also rising, particularly among the neonates. Due to differences in their biology, these species employ different antifungal resistance and virulence mechanisms and also induce dissimilar immune responses. Previously, it has been suggested that core virulence effecting transcription regulators could be attractive ligands for future antifungal drugs. Although the virulence regulatory mechanisms of C. albicans are well studied, less is known about similar mechanisms in C. parapsilosis. In order to search for potential targets for future antifungal drugs against this species, we analyzed the fungal transcriptome during host-pathogen interaction using an in vitro infection model. Selected genes with high expression levels were further examined through their respective null mutant strains, under conditions that mimic the host environment or influence pathogenicity. As a result, we identified several mutants with relevant pathogenicity affecting phenotypes. During the study we highlight three potentially tractable signaling regulators that influence C. parapsilosis pathogenicity in distinct mechanisms. During infection, CPAR2_100540 is responsible for nutrient acquisition, CPAR2_200390 for cell wall assembly and morphology switching and CPAR2_303700 for fungal viability.

Candida parapsilosis: from Genes to the Bedside

“…In these studies, RNAseq, together with phylogenetic and synteny analyses, was instrumental in pinpointing the right candidates among paralogous members of several gene families, including 138 paralogs of the major facilitator superfamily of transporters (MFS), by identifying those expressed in the presence of the substrate. Finally, the identification of C. parapsilosis transcripts expressed upon exposure to human macrophages was used to prioritize the construction of knockout mutants to study host-pathogen interactions (101). Notably, 84% of the 19 constructed knockout mutants showed a phenotype different from that of the wild type under conditions related to virulence and interaction with the human host.…”

“…This facilitated the generation of a collection of Ͼ100 strains deleted for transcription factors and protein kinases (127). Later studies used the same method for the generation of smaller mutant sets (101,136,137).…”

“…C. parapsilosis OCH1 also determines morphology, as deletion of this gene significantly decreases the amount of pseudohyphae under filamentous-growth-inducing conditions (170). Additional regulators of C. parapsilosis pseudohyphal growth include the ortholog of CaSPT3 (CPAR2_200390), which negatively regulates filamentous growth, whereas CPAR2_501400, equivalent to CaCWH41, is essential for pseudohyphal formation (101,171,172). Notably, CpEFG1, CpOCH1, and…”

Comparative transcriptomics of THP-1 monocytes in response to different pathogens

“…RNA sequencing data was obtained in its raw read format from the Sequence read archive (Leinonen, Sugawara, and Shumway, 2011), with the exception of the data for C. parapsilosis , which was provided by the authors of Toth et al (Tóth et al, 2017), the full list of sequence runs can be found in Table 1. A shell script to initiate the full download can be found at the github repository https://github.com/Gabaldonlab/THP1data.…”

“…(Reyes et al, 1999; Zakharova et al, 2010) as well as the protist Leishmania mexicana (Millar et al, 2015). In a recent study, Toth et al (Tóth et al, 2017) Investigated the response of the pathogenic yeast Candida parapsilosis to THP-1. Additionally, available data includes exposure to ethanol, calcitriol and Tissue-type Plasminogen Activator (TPA) (Barendsen, Mueller, and Chen, 1990).…”