Candida parapsilosis

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Description and significance

Candida parapsilosis is a fungal species that is responsible for several disease states in humans [1]. Among the many microbes found on human hands, C. parapsilosis is among the most prevalent fungal species [2]. This species is known to cause sepsis in those with compromised immune systems, neonates, intensive care patients, individuals with implanted devices, and individuals who have just recently undergone gastrointestinal surgery [2]. Researchers have found that as much as eight to fifteen percent of all infections procured by patients in hospitals have been attributed to C. parapsilosis [1]. Because of the lack of understanding about this taxon’s virulence mechanisms, treatment is difficult and not always effective [3]. It is therefore crucial for future research to focus on understanding the signaling pathways involved in infection and how these pathways are regulated since they are not well understood.

Classification

Higher order taxa

C. parapsilosis is a fungus belonging to the phylum Ascomycota [4]. C. parapsilosis is a member of the class Saccharomycetes and the order Saccharomycetales which are most commonly known as budding yeasts, meaning they can reproduce asexually through the process of mitosis when nutrients are abundant and sexually through production of haploid cells in meiosis when nutrients are not abundant [4][5]. C. parapsilosis is a member of the family Debaryomycetaceae, which are commonly associated with the yeast’s use of pseudohyphae to grow [4][6]. C. parapsilosis is a part of the genus Candida, which is most well known for its ability to cause disease in humans [7]. C. parapsilosis is also a member of the CTG clade, along with C. albicans, meaning that their CTG codon encodes for serine and not leucine [7].

Genome structure

Concrete information on the genomic structure of C. parapsilosis has yet to be discovered. The fungus contains mostly uncharacterized open reading frames (ORFs), making up about 98.95% of the protein-coding genes [8]. The rest of the genes code for rRNA, tRNA, and pseudogenes, which make up 1.05% of its protein-coding genes. It is also known that the majority of genes responsible for molecular function use hydrolase activity, they are most abundant in the cytoplasm, and are used for the regulation of biological processes [8].

Although other characteristics such as the G+C content and the total number of genes in the genome are still unavailable, a recent study points to the possibility of genomic variation within C. parapsilosis. Researchers used whole genome sequencing to analyze three sample strains of the fungus [9]. Compared to a control reference strain of C. parapsilosis, the three sample strains showed similar genetic characteristics in addition to high variation regions within each sequence. The strains contained many ALS genes that code for cell-surface glycoproteins, which varied slightly across all three samples [9]. The discovery of the differences in these abundant ALS genes indicate that C. parapsilosis is capable of genetic recombination, resulting in high variability within the genome of each strain. Although researchers in this study were able to isolate strains, C. parapsilosis isolates are known for being genetically non-differentiable, and often need to be interpreted through advanced bioinformatic systems [9]. Additionally, C. parapsilosis contains many repetitive sequences within the one section of its genome that has been sequenced. This is another complication that researchers face when trying to sequence its entire genome. High copies of the same DNA sequences cannot be accurately assigned to a specific genomic location or function because they could have multiple roles within the entire genome [9].

Cell structure

C. parapsilosis primarily exists in a unicellular, budding state. However, it is also capable of forming pseudohyphae, which makes it appear to be dimorphic [1]. In the yeast phenotype, colonies appear smooth, and in the pseudohyphae phenotype the colonies appear concentric [1]. On a dextrose plate, C. parapsilosis forms white, creamy, shiny colonies composed of cylindrical cells [1].

Although the cellular composition of C. parapsilosis is not fully understood, it is suspected to be similar to a closely related species, Candida albicans [12]. The innermost layer of the cell wall is composed of chitin, a fibrous polysaccharide that enhances the rigidity of the membrane [12]. The outermost layer of the cell wall is covered in proteoglycans; specifically, mannose-rich arginine residues (N-linked mannans) and serine/threonine residues (O-linked mannans) [12]. N-linked and O-linked mannans play an important role in cell morphology, cell differentiation and host interactions. Loss of these mannans can dramatically reduce the virulence of C. parapsilosis [12].

Metabolic processes

In order to take in nutrients from the environment, C. parapsilosis releases various extracellular enzymes that breakdown large macromolecules into smaller molecules, thereby making them available for absorption [13]. Out of 172 C. parapsilosis isolates, 63% exhibit phospholipase activity [13]. This extracellular enzyme allows for the breakdown of phospholipids into free fatty acids, which are then used in cell metabolism. Additionally, 92% of C. parapsilosis isolates exhibit gelatinase activity and 47% exhibited caseinase activity [13]. Both gelatinase and caseinase are extracellular enzymes that degrade large proteins into amino acids which are also used in cell metabolism [13].

C. parapsilosis is capable of converting nutrients into energy by way of both oxidative phosphorylation and fermentation, although the specific complexes involved in each pathway are not fully understood. C. parapsilosis is capable of fermenting and assimilating a variety of sugars, as listed in Table 1 [14].

It is worth noting that metabolic activities of C. parapsilosis are directly related to its virulence capabilities. Many of the extracellular enzymes used to breakdown large macromolecules are vital for host invasion. Phospholipases are used to disrupt the ester linkages found in host cell membranes [13]. Proteases, like gelatinase and caseinase, play an important role in degrading the proteins found in host epithelial and mucosal barriers as well as degrading proteins involved the host immune response [13]. Additionally, glucose concentration is directly related to biofilm modulation in C. parapsilosis. Although the exact mechanism remains unknown, increased glucose metabolism leads to the upregulation of pathways involved in biofilm formation [14].

Table 1 [8]. Sugars fermented and assimilated by Candida parapsilosis.

	Fermentation “+” positive, “-“ negative	Assimilation “+” positive, “-“ negative
Glucose	+	+
Sucrose	+	+
Galactose	+	+
Lactose	-	-
Trehalose	+	+
Maltose	+	+
Rafinose	-	-

Ecology

C. parapsilosis is found to be a frequent inhabitant of human skin as well as many other environments and communities. This fungal species is known to live on other organisms like domestic animals and insects, and is also found to reside in soil and marine environments [1]. Moreover, C. parapsilosis is found in many geographic locations around the world; it has been isolated in North America, Europe, Latin America, Africa and Asia. The incidences of C. parapsilosis infection has increased globally since 1997 [1].

In addition to persisting among live organisms, C. parapsilosis has also been found to exist in man-made environments and household appliances. In a study by Dögen, et al., researchers investigated specific sites on 99 washing machines in different residences in Turkey to explore the prevalence of C. parapsilosis [15]. Their results indicated that C. parapsilosis was found to be residing among nearly a quarter of all washing machines [15].

Pathology

C. parapsilosis is a pathogenic fungus that is easily spread within susceptible populations of humans and animals. The fungus causes sepsis, endocarditis, endophthalmitis, fungemia, peritonitis, and arthritis in humans. It is most commonly found on prosthetic devices, catheters, and other medical tools that are touched by healthcare workers [10]. The virulence of C. parapsilosis is increased by the its ability to form biofilms on these medical devices and grow from prolonged attachment [1]. Furthermore, the fungus can easily spread from healthcare worker to patient if thorough hand-washing is not performed prior to contact [10].

In the body, C. parapsilosis colonizes around the implanted device and attaches to mucosal surfaces nearby. Biofilm production serves as protection and makes the microbe resistant to antifungal medications [10]. This makes it difficult for natural immune cells to fight off the fungus since they are unable to attach onto the slippery surface of the biofilm. Thus, C. parapsilosis is ultimately responsible for causing post-surgical complications and premature death in susceptible populations. The most at-risk population of contracting an infection are neonatal patients, intensive care patients, and immunocompromised patients [1]. Unlike other Candida species, such as C. albicans, C. parapsilosis is not an obligate pathogen and only causes candidiasis in these specific populations [7]. C. parapsilosis can also affect the immune systems of animals in a similar manner. Animals can ingest the pathogen from soil, insects, and other environmental sources, leading to infection and death [10].

In addition to C. parapsilosis’ ability to defend itself against the immune response and antifungal medication, it is also able to hide from detection [11]. Histopathology signatures for C. parapsilosis are useful in identifying the fungus’ infectious pathway. However, they are not always detected upon screening [11]. In one study, blood and lung cultures of neonates who died from a C. parapsilosis infection were analyzed for any histopathological signatures. Upon autopsy and immunostaining, 61% of the population was found to have significant fungal presence, but only 14 out of the 187 neonates were initially diagnosed with a C. parapsilosis induced infection [11]. The overwhelming prevalence of C. parapsilosis in the majority of the studied population went undetected by normal screening methods, showing that C. parapsilosis infections often go underdiagnosed.

Current Research

Current research is mostly centered on improving treatment outcomes for individuals infected by C. parapsilosis. Researchers in Japan performed a retrospective observational study from 2000-2010, investigating the susceptibility of C. parapsilosis isolates to antifungals and what other comorbidities existed for patients who did not survive the infection [16]. The study investigated patients with nosocomial candidemia who had prosthetic devices inserted. Researchers quantified antifungal susceptibility using minimum inhibitory concentration (MIC). The study concluded that the previous standard treatment for nosocomial candidemia could be modified to include echinocandins, as they were found to be successful in decreasing patient mortality [16].

A similar study investigated the human immune response to C. parapsilosis. This was done by comparing the concentration of cytokine responses exhibited by different Candida species when they stimulated peripheral blood mononuclear cells (PBMCs) [17]. The researchers found that C. parapsilosis-stimulated cells produced less interleukin 17 and 22 than that of C. albicans. They also found that inhibition of mitogen-activated protein kinases was necessary for the body to recognize that it had been infected by a Candida species [17].

References

[1] Trofa, D., Gácser, A., & Nosanchuk, J. D. (2008). Candida parapsilosis, an Emerging Fungal Pathogen. Clinical Microbiology Reviews, 21(4), 606–625. http://doi.org/10.1128/CMR.00013-08

[2] Silva S, Negri M, Henriques M, Oliveira R, Williams D, Azeredo J. 2012. Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiology Reviews. 36(2): pp. 288–305. https://doi.org/10.1111/j.1574-6976.2011.00278.x

[3] Papadimitriou-Olivgeris, M., Spiliopoulou, A., Kolonitsiou, F., Bartzavali, C., Lambropoulou, A., Xaplanteri, P., . . . Christofidou, M. (2018). Increasing incidence of candidaemia and shifting epidemiology in favor of Candida non-albicans in a 9-year period (2009–2017) in a university Greek hospital. Infection. doi:https://doi.org/10.1007/s15010-018-1217-2

[4] Candida parapsilosis. Retrieved from https://www-ncbi-nlm-nih-gov.ezproxy.bu.edu/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=5480&lvl=3&lin=f&keep=1&srchmode=1&unlock

[5] Duina, A., Miller, M., & Keeney, J. (2014). Budding yeast for budding geneticists: A Primer on the Saccharomyces Cerevisiae model system. Genetics, 197(1), 33-48. Retrieved from https://doi.org/10.1534/genetics.114.163188

[6] Hui, F., Ren, Y., Chen, L., Li, Y., Zhang, L., & Niu, Q. (2014). Molecular phylogenetic analysis reveals the new genus hemisphaericaspora of the family debaryomycetaceae. PLOS One. 9(7), e103737. Retrieved from https://doi.org/10.1371/journal.pone.0103737

[7] Turner, S., & Butler, G. (2014). The Candida pathogenic species complex. Cold Spring Harbor Perspectives in Medicine, 4(9). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143104/

[8] Skrzypek MS, Binkley J, Binkley G, Miyasato SR, Simison M, Sherlock G (2017). The Candida Genome Database (CGD): incorporation of Assembly 22, systematic identifiers and visualization of high throughput sequencing data. Nucleic Acids Res 45 (D1); D592-D596.

[9] Pryszcz, L.P., Németh, T., Gácser, A., Gabaldón, T. (2013). Unexpected Genomic Variability in Clinical and Environmental Strains of the Pathogenic Yeast Candida parapsilosis. Genome Biology and Evolution, 5(12), 2382–2392. https://doi.org/10.1093/gbe/evt185

[10] Wikipedia contributors. (2018, July 5). Candida parapsilosis. In Wikipedia, The Free Encyclopedia. Retrieved 15:52, September 20, 2018, from https://en.wikipedia.org/w/index.php?title=Candida_parapsilosis&oldid=848995454

[11] Hemedez, C., Trail-Burns, E., Mao, Q., Chu, S., Shaw, S.K., Bliss, J.M., Paepe, M.E. (2018). Pathology of Neonatal Non-albican Candidiasis: Autopsy Study and Literature Review. Pediatric and Developmental Pathology, 7(4), 655-673. https://doi.org/10.1177/1093526618798773

[12] Perez-Garcia LA, Csonka K, Flores-Carreon A, Estrada-Mata E, Mellado-Mojica E, Nemeth T, Lopez-Ramirez LA, Toth R, Lopez MG, Vizler C, Marton A, Toth A, Nosanchuk JD, Gacser A, Mora-Montes HM. 2016. Role of Protein Glycosylation in Candida parapsilosis Cell Wall Integrity and Host Interaction. Frontiers in Microbiology. 7(306): pp. 1-16. https://doi.org/10.3389/fmicb.2016.00306

[13] Neji S, Hadrich I, Trabelsi H, Abbes S, Cheikhrouhou F, Sellami H, Makni F, Ayadi A. 2017. Virulence factors, antifungal susceptibility and molecular mechanisms of azole resistance among Candida parapsilosis complex isolates recovered from clinical specimens. Journal of Biomedical Science. 24(67). https://doi.org/10.1186/s12929-017-0376-2

[14] Pereira L, Silva S, Ribeiro B, Henriques M, Azeredo J. 2015. Influence of glucose concentration on the structure and quantity of biofilms formed by Candida parpsilosis. FEMS Yeast Research. 15(5). https://doi.org/10.1093/femsyr/fov043

[15] Dögen, A., Sav, H., Gonca, S., Kaplan, E., Ilkit, M., Babič, M. N., . . . Sybren de Hoog, G. (2017). Candida parapsilosis in domestic laundry machines. International Society for Human and Animal Mycology,55, 813-819. doi:10.1093/mmy/myx008

[16] Hirai, Y., Asahata, S., Ainoda, Y., Goto, A., Fujita, T., & Totsuka, K. (2014). Nosocomial Candida parapsilosis candidaemia: Risk factors, antifungal susceptibility and outcome. Journal of Hospital Infection, 87(1), 54-58. doi://doi-org.ezproxy.bu.edu/10.1016/j.jhin.2014.02.006

[17] Toth, A., Csonka, K., Jacobs, C., Vagvolgyi, C., Nosanchuk, J. D., Netea, M. G., & Gacser, A.(2013). Candida albicans and Candida parapsilosis induce different T-cell responses in human peripheral blood mononuclear cells. Journal of Infectious Diseases, 208(4), 690-698. doi:10.1093/infdis/jit188

Edited by Natalia Aneiros, Dominick Milano, Sharmetha Ramanan and Quintashia Wilson, students of Jennifer Bhatnagar for BI 311 General Microbiology, 2018, Boston University.