Date Published: April 8, 2019
Publisher: Public Library of Science
Author(s): Jeniel E. Nett, Deborah A. Hogan.
The emerging fungal pathogen Candida auris is causing outbreaks of invasive disease in healthcare facilities around the world [1–4]. Isolates often exhibit resistance to multiple drug classes, and invasive disease carries an astonishingly high mortality rate, approaching 60% . The initial description of C. auris arose following the isolation of a novel species from the ear canal of a patient in a Japanese hospital . Since this report in 2009, cases have subsequently appeared in hospitals in South Korea, India, the Middle East, South Africa, and South America [6–10]. More recent reports reveal the spread of C. auris to North American and European healthcare facilities [3, 11]. Genomic analysis shows that the circulating strains cluster into distinct clades, which appear to have emerged independently . Retrospective analyses of Candida isolates collected from international sites in the decades leading to 2009 uncovered only rare cases of C. auris, confirming the recent emergence of this species [5, 10].
C. auris can cause invasive disease involving a variety of clinical niches [3, 5]. The most frequently reported site is the bloodstream, with isolation from the urinary or respiratory tract close behind . Despite the high frequency of most Candida species to cause oral or esophageal disease, C. auris is not frequently reported at these sites. A study by Pathirana and colleagues shed light on one reason for this apparent void. They examined activity of a salivary cationic peptide, histatin 5, against C. auris and found the vast majority of isolates to be highly sensitive, particularly those exhibiting antifungal resistance . Another intriguing observation is that a common risk factor for invasive candidiasis, neutropenia, has not been reported for C. auris infection, because this is a common risk for other Candida spp. [5, 6]. Invasive disease in the absence of neutropenia suggests that the host neutrophil response may not be adequate for control of C. auris.
Several groups have explored the pathogenicity of C. auris, employing a variety of model systems [11, 19, 25–28]. Initial reports utilized an invertebrate moth larvae (Galleria mellonella) model of invasive candidiasis [11, 19]. These studies examined C. auris strains collected in the United Kingdom and found them to be considerably more virulent than other nonfilamentous Candida isolates. A subset of C. auris exhibited pathogenicity similar to even the most virulent species, C. albicans and Candida tropicalis . Of note, the more virulent C. auris isolates grew in nonaggregative forms, in contrast to the less pathogenic strains that formed large aggregates. As these nonaggregative forms also tended toward more robust biofilm formation, it is intriguing to speculate clinical relevance for this phenotype .
A recent report questioned the efficacy of the phagocytic response against a C. auris strain collected from India . Neutrophils, key leukocytes for the control of invasive candidiasis, kill fungi through phagocytosis and the delivery of antimicrobial contents during neutrophil extracellular trap (NET) formation [29, 30]. However, human neutrophils were found to lack effective activity against C. auris. They failed to engage C. auris, phagocytose the yeast, or release NETs. When presented with both C. albicans and C. auris, human neutrophil exhibited a strong preference for engaging and killing C. albicans (Fig 1) . The phagocytes functioned normally against C. albicans but appeared to disregard C. auris. In vivo analysis of neutrophils in a zebrafish model of invasive candidiasis mimicked the phenotype.
Unlike other Candida species, C. auris has emerged as a nosocomial threat, exhibiting rapid person-to-person transmission and causing critical invasive disease. Recent investigations are just beginning to shed light on the mechanisms of pathogenicity for this deadly infection. In several models of invasive disease, strains of C. auris display virulence similar to that of the most virulent Candida species. The observation that neutrophils exhibit reduced activity against C. auris may contribute to poor outcomes for patients with invasive disease. However, the high mortality for invasive candidiasis likely also reflects the comorbidities and prolonged hospitalizations for this cohort. One promising finding is the efficacy of the C. albicans NDV-3A vaccine for protection against C. auris in mice . Prevention would be ideal for the vulnerable population of hospitalized patients.