Candida parapsilosis: An emerging pathogen developing its own identity

Keywords:

• Candida parapsilosis
• candidiasis
• host-defense
• macrophage
• neutrophil
• phagocytosis
• virulence

This article is referred to by:

Candida parapsilosis produces prostaglandins from exogenous arachidonic acid and OLE2 is not required for their synthesis

Candida species account for a sizeable proportion of healthcare-associated infections with an increasing frequency over the last decade.^1-3 Historically, C. albicans was the most frequent cause of these infections, accounting for 70–80% of isolates from infected patients.⁴ Accordingly, studies involving virulence attributes of C. albicans and its interactions with the host have dominated the Candida literature. However, infections caused by non-albicans species are increasing in frequency, and in many centers, these species (C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) have emerged as the leading cause of invasive candidiasis.^1,5 As the clinical importance of the non-albicans species has garnered attention, so have efforts to understand their biology. Importantly, these studies continue to identify important differences among non-albicans species and C. albicans, challenging the notion that lessons learned from study of C. albicans will be broadly applicable to other pathogenic Candida.

Recent epidemiologic surveys of invasive candidiasis have identified C. parapsilosis as the third most commonly isolated species, albeit with wide variation among centers, geographic region, and patient characteristics.^1,5 Notably, C. parapsilosis has a significantly higher prevalence in neonates than other at risk populations, suggesting a unique susceptibility of neonates to infection with this species.^6-8 In the previous issue, Grózer et al. compared C. parapsilosis to C. albicans in regard to its ability to produce prostaglandins from arachidonic acid and interrogated the role of OLE2 in the process.⁹ C. albicans produces prostaglandins, which are biologically active in mammalian cells and have immunomodulatory effects that may contribute to fungal virulence.¹⁰ The authors in the current study detected a variety of prostaglandin compounds produced by both C. albicans and C. parapsilosis when the yeast were cultured in the presence of arachidonic acid, with PGE₂ and PGD₂ at the highest concentrations for both species. However, disruption of the putative Δ9-desaturase gene, OLE2, which in C. albicans significantly decreases PGE₂ production,¹¹ had no effect on PGE₂ synthesis in C. parapsilosis. The OLE2-deficient strain did show alterations in fatty acid composition, however, suggesting a role in fatty acid biosynthesis. Finally, a role for OLE2 in virulence was suggested by the finding that the OLE2-deficient strain underwent phagocytosis and killing by human monocyte-derived macrophages with somewhat higher efficiency than wild-type C. parapsilosis. These findings add to existing literature supporting a role for fatty acid biosynthesis pathways in the virulence attributes of pathogenic fungi including Cryptococcus neoformans,¹² C. albicans,¹³ and C. parapsilosis.^14,15 Despite the similarities, however, this study highlights important differences between the species that may have relevance to unique attributes of these host-pathogen interactions.

As studies similar to these continue to gain momentum, host interactions unique to C. parapsilosis relative to C. albicans are increasingly being recognized. Studies from this same group have highlighted some key differences in both innate and adaptive immune responses to these related pathogens. Human macrophages undergo phagocytosis of C. parapsilosis with higher efficiency than C. albicans or C. glabrata, and murine J774.1 macrophages show faster migration toward C. parapsilosis.¹⁶ The organism is also able to survive and undergo replication within the macrophage. Investigation of the transcriptional response of murine macrophages to C. parapsilosis by microarray also demonstrated significant differences in the transcriptome following exposure compared to that of C. albicans.¹⁷ T-cell responses to C. parapsilosis and C. albicans are also quite unique. Whereas C. albicans induces a Th1-biased response, C. parapsilosis induces more of a Th2-type response characterized by higher amounts of IL-10 and less IFN-γ upon coincubation with human peripheral blood mononuclear cells (PBMCs). Additionally, coincubation of PBMCs with C. parapsilosis results in less Th17 differentiation that C. albicans, accompanied by lower production of IL-17 and IL-22.¹⁸

Other groups have documented additional key differences in how components of the innate immune system interact with these related species. Neutrophils have long been recognized to be key elements contributing to anti-fungal host defense. Like macrophages, human neutrophils also undergo phagocytosis of C. parapsilosis yeast with much higher efficiency than C. albicans yeast, resulting in increased toxicity to the former.¹⁹ The process is markedly faster in neutrophils than macrophages. In kinetic assays, phagocytosis rates had reached a plateau within 5–10 minutes of incubation,²⁰ whereas with macrophages phagocytosis was noted to continue beyond 3 hours.¹⁶ Neutrophils undergoing phagocytosis of each species likewise demonstrated differing morphology in scanning electron microscopic images, suggesting that different phagocytic pathways may be invoked by each species.²⁰ These studies also suggested a role for the S-type lectin, galectin-3, in the process of neutrophil phagocytosis. Indeed, galectin-3 deficient mice infected with C. albicans or C. parapsilosis showed increased disease susceptibility relative to wild-type mice, although the manifestations of disease differed between the 2 species.²¹

Host innate immune cells respond to pathogens by recognition of pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs). In the case of pathogenic fungi, PAMPs are largely comprised of cell wall components. “Mannan” refers to the collection of mannose polymers, covalently associated with protein, that make up the outermost layer of the fungal cell wall. Mannan is the major antigenic determinant of Candida species, and basic structural differences in the composition of mannan between C. albicans and C. parapsilosis have been previously defined.^22,23 Interactions between Candida mannan and various host PRRs are well described.²⁴ In some cases, differences in cellular response to C. parapsilosis relative to C. albicans have been noted that are likely attributable to unique PAMPs. For example, C. albicans is bound and internalized by dendritic cells (DC) through binding of N-linked mannan to DC-SIGN whereas C. parapsilosis interacts weakly.^25,26 In contrast, C. parapsilosis induces a “fungipod” by DC through binding to mannose receptor while C. albicans has a weaker effect.²⁷ Our understanding of how variability in cell surface makeup among species impacts host defense mechanisms is in its infancy and is an area ripe for investigation.

Investigation of similarities and differences in pathogenesis among the various species of Candida was facilitated by whole genome sequencing of C. parapsilosis and 5 other Candida species in 2009.²⁸ Methods for efficient gene disruption initially developed in C. albicans²⁹ have now been applied successfully to C. parapsilosis allowing efficient construction of targeted gene deletions.³⁰ Careful phenotypic analyses of deletion mutants in relevant gene families have begun to highlight key similarities and differences between C. parapsilosis and C. albicans that will be instrumental in defining the molecular aspects of their virulence.

The emergence of non-albicans species as increasingly important pathogens in invasive candidiasis is well documented in the literature and has captured the attention of the research community. Comparisons of virulence attributes and host-response to these species have begun to reveal both similarities as well as important differences in comparison to the wealth of information available from study of C. albicans. Differences among species likely underlie important differences in pathogenesis, host immune mechanisms, and clinical manifestations, and continued efforts in this area are necessary to optimize prevention and therapeutic strategies.

funding

The author was funded by Grant Number P20GM103537 from the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH), and by funds from the Oh Zopfi Professorship for Pediatrics and Perinatal Research from Brown University and Women & Infants Hospital of Rhode Island.