Exploring Candida auris in its habitat

Abstract

Candida auris colonizes human skin and causes life-threatening fungal bloodstream infections. In this issue of Cell Host & Microbe, Huang et al. introduce a murine model of C. auris skin colonization to explore the role of distinct clades, immune signaling pathways, antibiotics, and disinfectants on fungal persistence in or clearance from its habitat.

In 2009, the first clinical report identified Candida auris as a novel, often drug-resistant human fungal pathogen. In the intervening decade, the simultaneous appearance of four distinct clades (East Asian, South Asian, African, and South American) led to sporadic outbreaks of invasive disease, predominately in debilitated residents of long-term healthcare facilities and in hospitalized patients. The case-fatality ratio is approximately one in three, resulting in over 1,500 reported deaths in the United States since 2018. This high toll reflects the presence of comorbidities, compromised immune and mucosal barrier function, and the placement of life-sustaining medical devices or access channels (e.g., indwelling catheters, tracheostomies) in most affected individuals. Alarmingly, a subset of C. auris strains harbor resistance to the three most commonly used classes of antifungal drugs (azoles, polyenes, and echinocandins), leading to its inclusion and classification as an urgent threat on the 2019 US Centers for Disease Control and Prevention (CDC) Antibiotic Threats Report.

Although C. auris exhibits much lower virulence than other pathogenic Candida species, such as C. albicans, in systemic rodent models of infection (Xin et al., 2019), C. auris spreads in healthcare settings because the fungus can contaminate and cling to abiotic surfaces and medical devices, exemplified by an outbreak in the United Kingdom due to the inadequate sterilization of re-usable thermometers (Eyre et al., 2018). C. auris can resist decontamination by quaternary ammonium compounds, the most common class of disinfection agents. In addition, C. auris can asymptomatically colonize the skin and other body sites for prolonged periods, creating opportunity for rapid transmission among hospital patients and skilled nursing facility residents. The interplay of fungal, host, and environmental factors that contribute to C. auris persistence on abiotic, environmental, and human reservoirs remain poorly understood. To design interventions to mitigate C. auris spread and prevent invasive disease, it is critical to gain a detailed understanding of biological factors underlying colonization and tissue invasion, a critical step in pathogenesis. In this issue of Cell Host and Microbe, Huang et al. (2020) describe a C. auris skin colonization model in mice and begin to dissect determinants of fungal colonization in this niche.

The authors found that distinct highly clonal C. auris clades harboring thousands of single nucleotide polymorphisms within the ~12.5-MB genome have differential capacities to colonize murine skin. The highest colonization levels were observed with isolates from the African and South American clades, similar to epidemiologic observations in humans. Surprisingly, the authors observed that C. auris can enter the dermis without eliciting overt histopathologic signs of inflammation, expanding the C. auris habitat to deeper skin tissues than previously appreciated. In contrast, Malassezia species, skin-trophic fungal organisms and the causative agents of tinea versicolor, reside only within the corneal and the epidermal layer after epicutaneous administration in mice (Findley et al., 2013; Sparber et al., 2019). This finding could explain the re-occurrence of C. auris in patients who had repeated interval negative swabs, because these do not detect fungal organisms in deeper skin layers.

Similar to Malassezia species, C. auris induces interleukin-17A/F production by CD4⁺ and CD8⁺ T, γδ T, and innate lymphoid cells in the skin, a process that regulates fungal growth in this mucosal habitat. Consistent with this, the authors found that rag2^−/−il2r^−/− mice (that lack all T, B, and innate lymphocytes) and act1^−/− mice (that lack responsiveness to IL-17 receptor signaling) exhibited sustained C. auris colonization up to six months. However, the cellular and molecular requirements for C. auris-dependent IL-17 induction remain undefined, because Langerhans cells and Card9 signaling appear redundant for this process, distinct from observations in cutaneous C. albicans and Malassezia infection models (Sparber et al., 2019; Kashem et al., 2015).

Microbiota-mediated colonization resistance against Candida has been demonstrated in mice and humans with regard to intestinal niches (Fan et al., 2015; Zhai et al., 2020). Antibiotic-mediated depletion of anaerobic commensal bacteria is associated with fungal dysbiosis and intestinal domination by pathogenic Candida spp. Similarly, patients treated with carbapenem antibiotics have an increased risk for skin colonization with C. auris. The broad antibacterial spectrum of carbapenems against anaerobic and aerobic Gram-positive and Gram-negative bacteria suggests a possible role for bacterial colonization resistance against cutaneous C. auris colonization (Rossow et al., 2020). Interestingly, in Huang et al., the authors did not observe differences in C. auris skin colonization when mice were pre-treated with broad-spectrum antibacterial antibiotics. The reasons for this finding remain to be elucidated. First, C. auris residence in deeper dermal tissue might facilitate colonization because this habitat enables the fungus to evade colonization resistance mediated by bacteria (or other microbes) that reside predominately in more superficial layers of the skin. Second, skin bacteria associated with C. auris colonization resistance might not have been depleted by the antibiotic combinations tested in this study. Third, differences in composition between human and mouse skin commensal bacteria could be relevant if bacterial species that possess potent inhibitory functions against C. auris do not reside naturally on mouse skin. Thus, it would be informative to adapt the murine model of C. auris skin colonization to germ-free conditions and to explore bacterial-mediated colonization resistance to C. auris by using human skin commensal flora. Fourth, host factors, most likely IL-17-dependent immunity, could supersede the impact of microbiota-mediated colonization resistance for this organism.

The C. auris colonization model by Huang et al. will serve multiple purposes in translational research. It will facilitate in-depth studies on host and microbial factors that promote or inhibit C. auris skin colonization and on infection-control strategies, e.g., disinfectants, that are designed to counter C. auris persistence and transmission (Figure 1). As researchers unravel the complexity of microbial communities in the skin and their interplay with host immune factors, new findings will undoubtedly emerge, exemplified by fungal acquisition of bacterial flavohemoglobins to adapt to host antimicrobial compounds (Ianiri et al., 2020) that will shape our understanding of this niche. Understanding this interplay will form the basis to design targeted interventions to eradicate C. auris and other pathobionts in at-risk patients and to decrease the growing toll caused by these infections.

Figure 1. Factors that regulate C. auris in its skin habitat.

(A) Skin commensal bacteria could directly inhibit C. auris colonization, possibly via bacterial metabolites.

(B) Host Th17 responses mediate clearance of C. auris from skin.

(C) Disinfectants such as chlorhexidine gluconate reduce the skin C. auris burden.