Candida aurisphenotypic heterogeneity determines pathogenicityin vitro

Abstract

1Candida auris is an enigmatic yeast that provides substantial global risk in 2 healthcare facilities and intensive care units. A unique phenotype exhibited by 3 certain isolates of C. auris is their ability to form small clusters of cells known as 4 aggregates, which have been to a limited extent described in the context of 5 pathogenic traits. In this study, we screened several non-aggregative and 6 aggregative C. auris isolates for biofilm formation, where we observed a level of 7 heterogeneity amongst the different phenotypes. Next, we utilised an RNA-8 sequencing approach to investigate the transcriptional responses during biofilm 9 formation of a non-aggregative and aggregative isolate of the initial pool. 10 Observations from these analyses indicate unique transcriptional profiles in the two 11 isolates, with several genes identified relating to proteins involved in adhesion and 12 invasion of the host in other fungal species. From these findings we investigated for 13 the first time the fungal recognition and inflammatory responses of a three-14 dimensional skin epithelial model to these isolates. In these models, a wound was 15 induced to mimic a portal of entry for C. auris. We show both phenotypes elicited 16 minimal response in the model minus induction of the wound, yet in the wounded 17 tissue both phenotypes induced a greater response, with the aggregative isolate 18 more pro-inflammatory. This capacity of aggregative C. auris biofilms to generate 19 such responses in the wounded skin highlights how this opportunistic yeast is a high 20 risk within the intensive care environment where susceptible patients have multiple 21 indwelling lines.22 23

On the emergence, spread and resistance of Candida auris: host, pathogen and environmental tipping points

“…They get exposed to multiple broad spectrum antibiotics, antifungals and antiseptics [80,83]. All of these factors dramatically alter the normal host microbiota, creating favourable conditions for C. auris to colonize and invade [84]. Could the expansion of such dense clusters of susceptible hosts have possibly reached a tipping point in tandem with the changes in the environment, to allow C. auris to emerge as an efficient nosocomial pathogen?…”

Comparative Evaluations of the Pathogenesis of Candida auris Phenotypes and Candida albicans Using Clinically Relevant Murine Models of Infections

“…Although relatively little is known about how C. auris colonizes and causes disease, it is quite evident that this novel pathogen is strikingly distinct among yeasts ( 35 , 36 ). One unique growth feature in some isolates is cell aggregation ( 17 ) which was associated in vitro with differences in drug susceptibility, biofilm formation, and adhesin expression compared to nonaggregative isolates ( 1 , 11 , 14 , 17 , 32 ). Since previous studies have reported variable results for the biofilm-forming abilities of these isolates ( 14 , 17 , 18 ), we comparatively evaluated the 10 C. auris isolates in the CDC panel and selected the highest (0382-HBF) and lowest (0387-LBF) biofilm-forming isolates as phenotypic representatives for subsequent studies.…”

“…Interestingly, Pathirana et al ( 18 ) found that strain 0382-HBF is able to survive inside neutrophils significantly better than C. albicans , whereas strain 0387-LBF was susceptible to neutrophil killing. Additionally, unique fungal recognition and/or host profiles to different C. auris phenotypes were also reported using an in vitro skin wound model ( 1 ).…”

“… Candida auris has inexplicably and simultaneously emerged on six different continents as a nosocomial pathogen causing outbreaks in health care facilities in more than 40 countries ( 1 – 5 ), with mortality rates as high as 60% ( 6 , 7 ) ( https://www.cdc.gov/fungal/diseases/candidiasis/tracking-c-auris.html ). C. auris exhibits several concerning features compared to other Candida species; the most surprisingly feature is the efficient person-to-person transmission ( 8 ).…”

“…One interesting observation is an aggregative phenotype where daughter cells fail to be released after budding, causing isolates to grow in clumps (14,17,18). This aggregative form was shown to be linked to transcriptional changes in genes involved in cell adhesion to surfaces (1), inducible by exposure to antifungals in vitro (19), and less virulent than the nonaggregative phenotype in invertebrate infection models (14,17). Although yet to be investigated in vertebrate animal models, this unique growth feature could have potential clinical implications.…”