Candida albicans and Candida glabrata: global priority pathogens

Abstract

SUMMARYA significant increase in the incidence of Candida-mediated infections has been observed in the last decade, mainly due to rising numbers of susceptible individuals. Recently, the World Health Organization published its first fungal pathogen priority list, with Candida species listed in medium, high, and critical priority categories. This review is a synthesis of information and recent advances in our understanding of two of these species-Candida albicans and Candida glabrata. Of these, C. albicans is the most common cause of candidemia around the world and is categorized as a critical priority pathogen. C. glabrata is considered a high-priority pathogen and has become an increasingly important cause of candidemia in recent years. It is now the second most common causative agent of candidemia in many geographical regions. Despite their differences and phylogenetic divergence, they are successful as pathogens and commensals of humans. Both species can cause a broad variety of infections, ranging from superficial to potentially lethal systemic infections. While they share similarities in certain infection strategies, including tissue adhesion and invasion, they differ significantly in key aspects of their biology, interaction with immune cells, host damage strategies, and metabolic adaptations. Here we provide insights on key aspects of their biology, epidemiology, commensal and pathogenic lifestyles, interactions with the immune system, and antifungal resistance.

Keywords: Candida albicans; Candida glabrata; Nakaseomyces glabratus; WHO fungal priority list; antifungal resistance; commensalism; diagnostics; epidemiology; host response; pathogenicity.

Fig 1

Epidemiology and types of Candida infections. (A) Candida species causing superficial (black text) and systemic (red text) infections. Superficial infections affect the skin or mucosal surfaces of the body and are usually not life threatening. The most common superficial infections include vulvovaginal candidiasis and cutaneous candidiasis. Systemic infections can affect multiple organs including the heart, brain, and kidneys and can potentially lead to septic shock. (B) Epidemiology of Candida species based on SENTRY antimicrobial surveillance program from 2008 to 2009. C. albicans is the most prevalent global species, but variability in the prevalence of non-Candida albicans Candida species exists between different geographical regions. Additionally, the distribution of Candida species can differ in specific patient cohorts between countries.

Fig 2

Morphological plasticity in C. albicans and C. glabrata. (A) Morphological plasticity in C. albicans. Yeast and hyphae are probably the most well-investigated growth forms of C. albicans, with specific roles in commensalism and infection as described in the main text. Pseudohyphae are similarly regularly found in vitro and in vivo, but their role in C. albicans-host interaction remains largely unclear. Opaque and shmoo cells are both involved in mating, while both gray and hyphal cells are associated with different types of infections. Chlamydospores are formed on certain carbohydrate-rich media, and their role in vivo remains unclear. Wor1 and Efg1 are transcriptional regulators of C. albicans morphology, controlling the switch between white (yeast), GUT and opaque cells. (B) Morphotypes of C. albicans. Cell types shown include budding yeast cells, hyphae [reprinted from reference (143) with permission of Springer Nature], elongated yeasts forming pseudohyphae [reprinted from reference (36) with permission of Oxford University Press], chlamydospores formed from suspensor cells [reprinted from reference (37) with permission of John Wiley & Sons], enlarged Goliath cells [reprinted from reference (144) under a Creative Commons license], mating-competent opaque and gray phenotypes [reprinted from reference (179) with permission of Elsevier], elongated chemotactic shmoo-mating projections leading to tetraploid zygote [reprinted from reference (184)], and GUT cells suspected to form in the intestine [reprinted from reference (175) with permission of Springer Nature]. Scale bars represent 5 µm. Colony morphologies of C. albicans, namely, (A) O-smooth, (B) star, (C) ring, (D) irregular wrinkly, (E) stipple, (F) hat, (G) fuzzy, (H) R-smooth [reprinted from reference (166) with permission of AAAS]. (C) Morphotypes of C. glabrata. Cell types include budding yeasts and elongated pseudohyphae-like structures. Different colony phenotypes in the presence of CuSO₄ include white and very dark brown. Intermediate variations of brown colonies and wrinkled also exist but are not shown in the above image [reprinted from reference (182) with permission of the Microbiology Society].

Fig 3

Overview of selected pattern recognition receptors and their signaling pathways involved in immune recognition of Candida spp. C-type lectin receptors (mannose receptor, DC-SIGN, Dectin-1, Dectin-2, Dectin-3, and Mincle), toll-like receptors (TLR1, TLR2, TLR3, TLR4, TLR6, TLR7, and TLR9), and NOD-like receptors (NOD-2 and NLRP3) recognize conserved molecular patterns, termed pathogen-associated molecular patterns of Candida spp. (including mannan, β-1,3-glucan, chitin, candidalysin, secreted aspartic proteases, RNA, and DNA). Recognition induces downstream signaling via different pathways and transcription factors, such as NF-κB, AP1, IRFs, and NFAT, and activation of the immune response. MR, mannose receptor; DC-SIGN, dendritic cell-specific ICAM3-grabbing non-integrin; Mincle, macrophage-inducible Ca2⁺-dependent lectin receptor; TLR, Toll-like receptor; FcRγ, Fc receptor γ chain; NOD-2, nucleotide-binding oligomerization domain-containing 2; NLRP3, NLR family pyrin domain-containing 3; PLM, phopholipomannan; Sap, secreted aspartic protease; SYK, spleen tyrosine kinase; PKCδ, protein kinase Cδ; PLCγ, phospholipase C γ; CARD9, caspase activation and recruitment domain-containing 9; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; Bcl10, B-cell lymphoma/leukemia 10; MyD88, myeloid differentiation primary response 88; IRAK, interleukin-1 receptor-associated kinase; TRAF, TNF receptor associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β; MAPK, mitogen-activated protein kinase; IL, interleukin; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor kappa-light-chain enhancer of activated B cells; AP1, activating protein-1; IRF, interferon regulatory factor.

Fig 4

From commensal to pathogen. C. albicans and C. glabrata can reside in the human body as commensals in balance with the microbiome. C. albicans can be found as both yeast and hyphae on the gut mucosal surfaces, and hyphal-associated genes, e.g., UME6, have been shown to play an important role during commensalism. The iron-rich environment of the gut leads to downregulation of iron acquisition processes to avoid toxicity. During commensalism, the host cells activate the NF-κB pathway, independent of the fungal morphology. Immunosuppression, the use of antibiotics, and physical damage of the epithelial barrier are among the predisposing factors for Candida infections. C. albicans adheres to epithelial cells using adhesins such as Als3, followed by invasion via induced endocytosis (triggered by Als3) or active penetration (by physical forces), leading to either transcellular or paracellular invasion. The transcellular route can cause severe candidalysin-mediated cellular damage. However, moderate damage can be repaired by epithelial cells. In addition to candidalysin, the fungus can secrete an arsenal of hydrolases (e.g., proteases and lipases). C. glabrata invades the epithelial barrier either via damaged barriers or by exploiting invading C. albicans hyphae in co-infections. Epithelial cells invaded by hyphal cells and damaged by candidalysin activate the MKP1/c-FOS pathway, which leads to the production of cytokines and attraction of phagocytes. Once inside the lamina propria, both fungi can get phagocytosed by resident macrophages via recognition of PAMPs (β-1,3-glucan and mannan). Inside the phagosome, fungal cells use superoxide dismutases to detoxify reactive oxygen species. Phagocytosis of C. albicans cells by macrophages triggers the production of high levels of several cytokines, while phagocytosis of C. glabrata causes the secretion of only low levels of granulocyte-macrophage colony-stimulating factor (GM-CSF). Internalized C. albicans cells produce hyphae, induce pyroptosis, and secrete candidalysin, which lead to the activation of the NLRP3 inflammasome and escape from the phagocyte. Cytokine production from both epithelial cells and macrophages recruits further phagocytes (neutrophils, macrophages, and dendritic cells) from the bloodstream. Phagocytosis by dendritic cells activates Th17 immunity and the production of IL-17 and IL-22. IL-17 promotes neutrophil trafficking, and IL-22 contributes to integrity of the epithelial barrier and production of antimicrobial peptides. C. albicans can further adhere to the endothelium and invade and translocate from there to cause bloodstream infections.