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      Don't Forget the Fungi When Considering Global Catastrophic Biorisks

      Health Security

      Mary Ann Liebert, Inc.

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          Abstract

          When it comes to biodefense and preparedness, the fungal kingdom is often a late afterthought. For example, among the original agents in the select agents list that were pathogenic for humans, only one fungus, Coccidioides immitis, was included, but the same organism was initially left out of the NIH priority agents list. This made laboratories working on this important pathogenic fungus subject to all the select agent regulations without the benefits of being able to apply for biodefense money. Although in recent years this fungus was taken off the select agents list and added to the NIH priority list, this anecdote is evocative of the way that this fungal kingdom is often forgotten when considering global catastrophic biological risks (GCBRs). In fairness to policymakers and preparedness experts, there has always been great concern about fungal threats to agriculture. However, when it comes to humans and animals, the potential threats from the fungal world are often ignored. Part of this obliviousness reflects the fact that fungal diseases are generally not communicable among humans and that immunologically intact humans are seldom susceptible to invasive mycoses. Hence, humanity does not have an experience with fungal pathogens comparable to the types of plagues caused by viral and bacterial diseases and consequently tends to ignore the fungal kingdom when assessing threats. The blind spot with regard to fungi is paradoxical given that fungal pathogens are currently devastating entire ecosystems. 1 Examples of the calamities caused by fungi include: (1) the extinction of numerous amphibian species as a result of infection with a chytrid fungus; (2) the decimation of North American bats by fungal disease new to the Americas; and (3) salamander, turtle, and snake die-offs from new fungal diseases. In general, humans and most mammals are remarkably resistant to invasive fungal diseases. The source of this resistance is believed to be a combination of adaptive immunity and endothermy, which effectively creates a thermal restriction zone that excludes the majority of fungal species. 2 However, the prevalence of fungal diseases can increase dramatically in human populations when there is an impairment of immunity, as evident from the high prevalence of cryptococcosis, candidiasis, and histoplasmosis in patients with AIDS. In fact, fungal diseases are now quite common, as a combination of medical progress, which often comes at the price of impaired immunity, and the global cataclysm of the HIV epidemic. With regard to the latter, cryptococcosis is now one of the major causes of death in sub-Saharan Africa, given the high prevalence of HIV infection in those populations. 3 In the past few years we have witnessed the emergence of a new fungal pathogen in Candida auris. This organism is associated with systemic infections that are resistant to many of the available antifungal drugs. 4 C. auris may be a harbinger of things to come. The low susceptibility of mammals to fungal diseases is determined largely by the temperature gradient between mammalian temperatures and temperatures tolerated by most fungal species. 5 However, as the world warms with climate change, many fungal species with the potential for pathogenicity in mammals will adapt to higher temperatures and could thus pose threats to human health. 6 There is an old adage that generals often prepare to fight the last war. This adage is relevant because most analysis of biological threats is heavily weighted toward concern for those viral and bacterial risks that we know about—the last wars. As we prepare to confront global catastrophic biorisks, we must consider the possibility that new threats from the fungal kingdom will be the future wars.

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          Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally

          Candidiasis, which includes both superficial infections and invasive disease, is the most common cause of fungal infection worldwide. Candida bloodstream infections (BSI) cause significant mortality and elicit a major threat to intensive care unit (ICU) patients [1]. The annual global burden of Candida spp. BSIs is about 400,000 cases, with most cases reported from the developed world. Although Candida albicans remains the most frequently isolated Candida species in the clinical setting, in some countries, a marked shift towards species of Candida that have increased resistance to azoles such as fluconazole (FLU), the standard antifungal drug of choice in many countries, and to the recently introduced antifungals known as echinocandins, is reported. Several species of non-albicans Candida, such as C. tropicalis, C. glabrata, and C. parapsilosis, are well-recognized pathogens in BSIs in different geographic locations. More recently, Candida auris, a multidrug-resistant (MDR) yeast that exhibits resistance to FLU and markedly variable susceptibility to other azoles, amphotericin B (AMB), and echinocandins, has globally emerged as a nosocomial pathogen (Fig 1) [2–20]. Alarmingly, in a span of only 7 years, this yeast, which is difficult to treat and displays clonal inter- and intra-hospital transmission, has become widespread across several countries, causing a broad range of healthcare-associated invasive infections [4, 5, 10, 12, 21, 22]. 10.1371/journal.ppat.1006290.g001 Fig 1 A global map depicting rapid emergence of multidrug-resistant clinical Candida auris strains in 5 continents. The value in parentheses denotes the year of report of C. auris from the respective country or state. Why is C. auris often misidentified in the routine microbiology laboratory? In 2009, a novel Candida species, C. auris, in the C. haemulonii complex (Metchnikowiaceae), was first described from a patient in Japan after its isolation from the external ear canal [23]. The species exhibits a close phylogenetic relationship to C. haemulonii and is differentiated based on sequence analysis of the D1/D2 domain of the large ribosomal subunit (LSU) of 26S rRNA gene and the internal transcribed spacer (ITS) regions of the nuclear rRNA gene operon [23]. The first 3 cases of nosocomial fungemia due to C. auris reported in 2011 from South Korea highlighted the fact that this yeast is commonly misidentified as C. haemulonii and Rhodotorula glutinis by the commercial identification systems VITEK (BioMérieux, Marcy l’Etoile, France) and API-20C AUX (BioMérieux), respectively [3]. These systems involve precast panels of assimilation/growth tests using sets of carbon and nitrogen compounds and are still widely used for routine identification of yeasts. A comprehensive study from India investigated C. auris prevalence among 102 clinical isolates previously identified as C. haemulonii or C. famata with the VITEK system and found that 88.2% of the isolates were C. auris, as confirmed by ITS sequencing [9]. It is evident from several studies published recently that C. auris in routine microbiology laboratories remains an unnoticed pathogen, as 90% of the isolates characterized by commercial biochemical identification systems are misidentified primarily because of a lack of the yeast in their databases [3–9, 12, 16–19, 24, 25]. Different biochemical systems are used in microbiology laboratories, and the majority of them listed in Table 1 misidentify C. auris. A recent study on validating the identification of C. auris with 4 biochemical identification platforms found that all C. auris isolates were misidentified as R. glutinis by API-20C AUX, as C. haemulonii (except 1, as C. catenulata) by Phoenix (BD-Diagnostics, Sparks, MD), as C. haemulonii by VITEK, and as C. famata, C. lusitaniae, C. guilliermondii, or C. parapsilosis by MicroScan (Beckman Coulter, Pasadena, CA) [25] (Table 1). However, Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) is considered a more rapid and robust diagnostic technique for C. auris identification [9, 10, 13, 16]. Currently, the MALDI-TOF MS approach is commercialized by mainly 2 manufacturers, namely MALDI Biotyper (Bruker-Daltonics, Bremen, Germany) and VITEK MS (BioMérieux). The MALDI Biotyper (Bruker-Daltonics) has a database library that contains spectra of 3 strains of C. auris: 2 from Korea and 1 from Japan. Although both the Bruker-Biotyper and VITEK-MS MALDI-TOF systems lack C. auris entries in the FDA-approved libraries, the research-use-only libraries contain the C. auris database in both MALDI-TOF MS systems [25]. Due to the fact that this yeast is MDR, it is important to identify these species correctly in order to provide optimal patient care. 10.1371/journal.ppat.1006290.t001 Table 1 Worldwide reports of Candida auris along with their misidentification using commercial systems and frequency of antifungal resistance. Country Number of Candida auris isolates Sample (number) Biochemical misidentification (System) Molecular/MALDI-TOF MS identification Number of isolates Year of publication [References] FLU(≥32 μg/ml) ITC(≥1 μg/ml) VRC(≥2 μg/ml) Echinocandins(≥8 μg/ml) AMB(>1 μg/ml) Japan 1 Ear discharge ND ITS, D1D2 ND ND ND ND ND 2009 [23] Korea 15 Ear discharge ND ITS, D1D2 8 8 2 none 9 2009 [2] South Korea 6 Blood C. haemulonii (VITEK), Rhodotorula glutinis (API20C-AUX) ITS, D1D2 4 2 none none 3 2011 [3] India 12 Blood C. haemulonii, C. famata (VITEK); C. sake (API20C-AUX) ITS, D1D2 10 none none none none 2013 [4] 15 Blood (7), CVC tip (3), Excised tissue (3), BAL (1), pus (1) C. haemulonii (VITEK) ITS 15 none 7 none none 2014 [5] 4 Blood (1), urine (1), pericardial fluid (1), BAL (1) C. haemulonii (VITEK); C. sake (API20C-AUX) ITS, D1D2 4 none none none none 2014 [6] 102 Blood (78), tissue (4), pleural fluid (6), peritoneal fluid (7), urine (4), sputum (3) C. haemulonii/C. famata (VITEK) ITS, MALDI-TOF MS 80 none 32 none 14 2015 [9] 51 Blood Not mentioned ITS, D1D2 49 3 9 none 10 2017 [19] India, South Africa, Korea, Japan, Brazil 104: 90 India (I), 6 South Africa (SA), 5 Brazil (B), 2 Korea (K), 1 Japan (J) Blood (n = 89; 78 I, 6 SA, 5 B), peritoneal and pleural fluid (5), invasive infections (4), urine (1), sputum (2) C. haemulonii (VITEK) ITS, D1D2, MALDI-TOF MS 5 (SA); 5 (B); 1 (K); none (J) None (SA); none (B); 1 (K); none (J) 1 (SA); 5 (B); 1 (K); none (J) none (SA); none (B); none (K); none (J) none (SA); 3 (B); none (K); none (J) 2016 [10] a Kuwait 1 Blood C. haemulonii (VITEK) ITS, D1D2 1 ND none none none 2015 [8] Israel 6 Blood (5), urine (1) C. haemulonii (VITEK) ITS, D1D2 6 none none none 6 2017 [18] Spain 8 Blood (4), catheter tip (4) Saccharomyces cerevisiae (AuxaColor 2); C. sake (API20C-AUX); C. lusitaniae, C. haemulonii (VITEK) ITS 8 none 8 none none 2017 [17] UK 12 Blood, sputum, CSF, pleural fluid, arterial line, pustule swab, wound swab, femoral line ITS, D1D2, MALDI-TOF MS 5 ND 1 none none 2016 [11] 50 Blood (16), wound (3), urinary catheter (1), unknown site with invasive candidiasis (2), colonization (28) b MALDI-TOF MS 50 ND ND none Range 0.5–2 μg/ml 2016 [13] Kenya 21 Blood C. haemulonii (VITEK) ITS - - - - - 2014 [24] South Africa 4 Blood C. haemulonii (VITEK) and R. glutinis (API20C-AUX) ITS, D1D2 4 none 1 none none 2014 [7] US 7 Blood (5), urine (1), external ear canal (1) Whole genome sequencing 5 c ND ND 1 c 1 c 2016 [14] CDC Collaborative Project [Pakistan (n = 18), India (n = 19), South Africa, (n = 10), Venezuela (n = 5), Japan (n = 1)] 54 Blood (27), urine (10), soft tissue (5), other sites (12) D1D2, Whole genome sequencing 50 Range 0.125–2 μg/ml 29 4 19 2017 [15] US 10 NA R. glutinis (API20C-AUX); C. haemulonii, C. catenulata (BD Phoenix); C. haemulonii (VITEK); C. famata, C. lusitaniae, C. guilliermondii, or C. parapsilosis (MicroScan) ITS, D1D2, MALDI-TOF MS ND ND ND ND ND 2017 [25] US, tested strains from Germany (n = 2), India (n = 11), Korea (n = 2), Japan (n = 1) 16 Blood (15), ear (1) Unidentified (API20C-AUX) ITS 8 5 5 d none 12 e , 16 d 2017 [20] Venezuela 18 Blood C. haemulonii (VITEK) ITS 18 ND 18 none Range 1–2 μg/ml 2016 [12] Colombia 17 Blood (13) peritoneal fluid (1), CSF (1), bone (1), urine (1) C. haemulonii (VITEK, Phoenix); C. tropicalis (MicroScan Walkaway); C. famata (API Candida); C. albicans (MicroScanautoSCAN); C. tropicalis (MicroScan Walkaway)/ C. famata (API Candida); C. albicans (MicroScanAutoSCAN) MALDI-TOF MS 10 ND 4 none 11 2017 [16] Abbreviations: -, not clear in the abstract; AMB, amphotericin B; BAL, bronchoalveolar lavage; CDC, US Centers for Disease Control and Prevention; CSF, cerebral spinal fluid; CVC tip, central venous catheter tip; FLU, fluconazole; ITC, itraconazole; ITS, internal transcribed spacer; MALDI-TOF MS, Matrix- assisted laser desorption ionization–time of flight mass spectrometry; MIC, minimum inhibitory concentration; ND, not done; VRC, voriconazole. aAntifungal susceptibility testing data of Indian isolates is same as reported by Kathuria et al., 2015. b Colonization with C. auris was defined as culture-positive skin, oropharynx, vascular line exit site, respiratory, and urinary tract without clinical signs of Candida infection. cMIC value not given. dMICs read after 48 hours. eMICs read after 24 hours. Does genetic predisposition make C. auris virulent? A recently published draft genome of C. auris shows that it has a genome size of approximately 12.3 Mb [26, 27]. A significant percentage of genes in C. auris are devoted to central metabolism, a property that is common to pathogenic Candida and crucial for adaptation to divergent environments. In addition, C. auris shares numerous virulence attributes with C. albicans, including genes and pathways involved in cell wall modelling and nutrient acquisition, histidine kinase-2 component systems, iron acquisition, tissue invasion, enzyme secretion, and multidrug efflux [21, 26, 27]. However, in vitro results in a single study that tested the production of phospholipase and secreted proteinase in multiple isolates of C. auris from different geographical regions showed that both secreted proteinase and phospholipase production was strain dependent. The phospholipase activity and secreted proteinase were detected in 37.5% and 64% of the tested isolates, respectively [20]. In general, the tested C. auris strains tended to have weak phospholipase activity, with the majority of isolates being non-phospholipase producers [20]. Furthermore, a significant portion of the C. auris genome encodes the ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporter families along with drug transporters that may explain the exceptional multidrug resistance in this pathogen [21, 27]. ABC-type efflux activity by Rhodamine 6G transport was significantly greater among C. auris than C. glabrata isolates, suggesting the intrinsic resistance of C. auris to azoles [18]. Interestingly, comparison of whole genome sequencing (WGS) data shows C. auris to be a close phylogenetic relative of C. lusitaniae, a species recognized for intrinsic antifungal resistance [21, 27]. C. auris also demonstrates thermotolerance, growing optimally at 37°C and maintaining viability at up to 42°C, salt tolerance, and cell aggregation into large, difficult-to-disperse clusters, which may help some strains to persist in the hospital environment [11, 23]. In a Galleria mellonella model, the aggregate-forming isolates exhibit significantly less pathogenicity than their non-aggregating counterparts [11]. Importantly, the non-aggregating isolates exhibited pathogenicity comparable to that of C. albicans, which is the most pathogenic member of the genus [11]. However, it is important to mention here that the observations made in this study are yet to be correlated with clinical cases and thus, assuming the same results in patients, need further experimentation. Furthermore, the virulence of C. auris tested in a mouse model of hematogenous-disseminated candidiasis showed distinct yeast cell aggregates in the kidneys of mice, with lethal C. auris infection suggesting that aggregation might be a mode of immune evasion and persistence in tissue [18]. Another significant factor involved in C. auris virulence is its ability to differentially adhere to polymeric surfaces, form biofilms, and resist antifungal agents that are active against its planktonic counterparts [28]. However, a more recent study reported that C. auris biofilms were significantly thinner, i.e., exhibited 50% thickness compared to C. albicans biofilm [20]. Also, C. auris exhibits minimal ability to adhere to silicone elastomer (a representative catheter material) relative to C. albicans [20]. C. auris’s weak adherence ability suggests that it is likely to play some role in catheter-associated candidiasis but not a large one, in contrast to C. albicans and C. parapsilosis, which are known to cause such infections [20]. Although, C. auris expresses several virulence factors, albeit to a lesser extent than C. albicans and in a strain-dependent manner [20]. The past and present of C. auris: Is the emergence of C. auris a menace to public health? In 2009, 15 isolates of C. auris were recovered from the ear canals of patients suffering from chronic otitis media in South Korea [2]. Most of these isolates showed a reduced susceptibility to AMB and azole antifungals. This report was followed by the first 3 cases of nosocomial fungemia caused by C. auris from South Korea [3]. The latter study reported that the earliest isolate of C. auris was found in 1996 in the Korean isolate collection [3]. All 3 patients had persistent fungemia for 10 to 31 days, and 2 patients who received FLU therapy followed by AMB showed therapeutic failure and had fatal outcome. Subsequently, 2 larger series of candidemia and deep-seated infections from India in 2013 and 2014 clearly showed that clonal strains of MDR C. auris had emerged in 3 hospitals [4, 5]. The isolates were resistant to FLU and 5-flucytosine (FC) and had elevated minimum inhibitory concentrations (MICs) of voriconazole (VRC) and caspofungin (CFG) [4, 5]. The most worrisome findings were persistent candidemia and high attributable mortality rates [4, 5]. C. auris accounted for >5% of candidemia in a national ICUs survey and up to 30% of candidemia at individual hospitals in India [4, 19]. In the subsequent 2 years, several reports of hospital-associated infections emerged from South Africa, United Kingdom, Venezuela, Colombia, United States, Pakistan, Israel, Kenya, and Spain [7, 11–18, 24]. Table 1 lists several countries reporting C. auris infection published so far across 5 continents. A collaborative project undertaken by the US Centers for Disease Control and Prevention (CDC) to understand the global emergence and epidemiology of C. auris reported that isolates from 54 patients with C. auris infection from Pakistan, India, South Africa, and Venezuela showed that 93% of isolates were resistant to FLU, 35% to AMB, and 7% to echinocandins; 41% were resistant to 2 antifungal classes, and 4% were resistant to 3 classes [15]. The fact that this yeast exhibits MDR clonal strains that are nosocomially transmitted is unusual in other Candida species [3, 5, 21]. Therefore, the possible threat of rapid spread in affected countries and its emergence in unaffected countries will not only challenge clinicians for its effective therapeutic management but will also bring high economic burden, especially to countries in resource-limited settings where modern identification facilities and access to antifungals other than FLU are limited. What are the drivers of clonal transmission and nosocomial outbreaks of C. auris? There is increasing evidence that suggests likely transmission of C. auris in healthcare settings. Recent reports highlight the persistent colonization by C. auris of hospital environments and multiple body-sites of patients, leading to high transmissibility and protracted outbreaks [13, 14]. A large outbreak of 50 C. auris cases in a London cardio-thoracic center between April 2015 and July 2016 showed persistent presence of the yeast around bed-space areas [13]. Genotyping with amplified fragment length polymorphism (AFLP) demonstrated that C. auris isolates clustered. Similarly, the investigation of the first 7 cases of C. auris infection identified in the US, which occurred between May 2013 and August 2016, showed colonization with C. auris on skin and other body sites weeks to months after their initial infection, which could possibly lead to contamination of the healthcare environment and pose a risk of continuous transmission [14]. Furthermore, C. auris was isolated from samples taken from the mattress, bedside table, bed rail, chair, and windowsill [14]. WGS results demonstrate that isolates from patients admitted to the same hospital in New Jersey were nearly identical, as were isolates from patients admitted to the same Illinois hospital [14]. Also, in the London outbreak, a healthcare worker caring for a heavily C. auris–colonized patient had a C. auris–positive nose swab [13]. Effective implementation of strict infection-prevention control measures are required to prevent transmission of C. auris. These include isolation of patients and their contacts, wearing of personal protective clothing by healthcare workers, screening of patients on affected wards, skin decontamination with chlorhexidine, environmental cleaning with chlorine-based reagents, and terminal decontamination with hydrogen peroxide vapor or ultraviolet (UV) light [13, 29]. Enhanced terminal cleaning with UV light has recently been shown to reduce infections with many nosocomial pathogens and might also be of use for preventing C. auris transmission [30]. Previously, several geographically related clusters have been reported from South Korea [2, 3], India [4, 5, 10], South Africa [10], Pakistan [15], and hospitals in Latin America [12, 16]. Clonality within C. auris has been shown using AFLP, multilocus sequence typing, and MALDI-TOF MS among strains in India, South Africa, and Brazil [10]. A recent study applying WGS demonstrated highly related C. auris isolates in 4 unrelated and geographically separated Indian hospitals, suggesting that this pathogen exhibits a low diversity [21]. A large-scale application of WGS analysis suggests recent independent and nearly simultaneous emergence of different clonal populations on 3 continents, demonstrating highly related C. auris isolates in the same geographic areas [15]. So far, no reservoir of C. auris has been identified, although future studies on its isolation from animals, plants, and water sources are warranted. Is antifungal resistance in C. auris a therapeutic challenge? Patients with C. auris infections have risk factors similar to those of other Candida spp. infections, including abdominal surgery (25%–77%), broad-spectrum antibiotics (25%–100%), ICU admission (58%), diabetes mellitus (18%), presence of central venous catheters (25%–94%), and malignancies (11%–43%) [3–5, 7, 12, 14–16]. The overall crude in-hospital mortality rate of C. auris candidemia ranges from 30% to 60%, and infections typically occur several weeks (10‒50 days) after admission [4, 5, 10, 12, 13]. C. auris invasive infections represent a therapeutic challenge, and no consensus exists for optimal treatment. A few studies report breakthrough fungemia while on FLU, and this correlates with commonly reported high MICs (>32 μg/ml), suggesting intrinsic resistance against this drug [3–5]. Although epidemiological cutoff values (ECVs) or clinical breakpoints are not yet defined for C. auris, newer azoles such as posaconazole (range, 0.06–1 μg/ml) and isavuconazole (range, 2 μg/ml) MICs [9, 15]. Up till now, echinocandin resistance is noted in fewer isolates (2%–8%) [9, 14, 15], but almost half of isolates are MDR (resistant to ≥2 antifungal classes), and a low number (4%) exhibit resistance to all classes of antifungals [2, 9, 12, 15, 16, 19]. Echinocandins remain the first-line therapy for C. auris infections, provided that specific susceptibility testing is undertaken at the earliest opportunity. Although CFG is normally highly effective against Candida biofilms, a recent report demonstrated that CFG was predominately inactive against C. auris biofilms [29]. FC (MIC50, 0.125–1 μg/ml) is a treatment option in renal tract or urinary tract infections, as the echinocandins fail to achieve therapeutic concentrations in urine [4, 5, 7, 9, 11–13, 15, 18]. Also, a novel drug, SCY-078, which is the first orally bioavailable 1, 3-β-D-glucan synthesis inhibitor, has been shown to possess potent activity against various Candida spp. and exhibit potent antifungal activity against C. auris isolates [20]. Furthermore, SCY-078 showed growth-inhibition and anti-biofilm activity and could be an important antifungal to treat this MDR species [20]. At present, the mechanism of antifungal resistance in C. auris is unclear. The recently published draft genome of C. auris revealed the presence of single copies of ERG3, ERG11, FKS1, FKS2, and FKS3 genes [21]. Detection of azole-resistant mutations by comparing ERG11 amino acid sequences between C. albicans and C. auris showed that alterations at azole-resistance codons in C. albicans were present in C. auris isolates [15]. These substitutions were strongly associated with country-wise–specific geographic clades [15]. Resistance is probably inducible under antifungal pressure, resulting in rapid mutational changes. However, future studies with emphasis on several molecular mechanisms, including efflux and transporters, could provide insight on C. auris resistance. What are the important things that we still need to learn about C. auris? We are just beginning to know the epidemiology and behavior of C. auris, but at the present, far more gaps exist in our knowledge. The earliest findings of C. auris are from 1996. The pertinent question remains whether this pathogen existed far earlier than 1996, and we were just unable to identify it. The latter is less plausible because many centers have reviewed archived isolate collections that have not shown any isolates of C. auris before 1996. We also do not know why C. auris is independently, almost simultaneously, emerging in so many places worldwide. It has been shown that there is a profound phylo-geographic structure with large genetic differences among geographic clades and high clonality within the geographic clades. However, a common characteristic is the high level of antifungal resistance, which is rare in other Candida spp. C. auris is the only species in which several isolates have been identified with resistance to all 4 classes of human antifungal drugs. It seems reasonable to opine that changes or misuse of antifungal drugs is one of the factors, although no specific risk factors for acquiring C. auris seem to exist. What we do know is that environmental factors probably play a role in outbreaks in healthcare settings that include prolonged survival in healthcare environments, probably due to skin colonization of patients and asymptomatic carriers. It is obvious that future research is warranted on multiple aspects of C. auris, which seems to have the typical characteristics of well-known, healthcare-associated pathogens such as carbapenemase-producing gram-negatives, Clostridium difficile, vancomycin-resistant Enterococcus (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). Given the behavior of the latter 4, a further spread of C. auris in healthcare settings on a worldwide scale is expected. C. auris worldwide emergence has prompted the CDC, (http://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html [last accessed February 2017]), Public Health England (PHE), London (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/534174/Guidance_Candida__auris.pdf [last accessed February 2017]), and the European Centre for Disease Prevention and Control (ECDC), Europe (http://ecdc.europa.eu/en/publications/Publications/Candida-in-healthcare-settings_19-Dec-2016.pdf) to issue health alerts for strict vigilance of C. auris cases. International collaborative consortia and timely efforts by the medical community are indispensable in controlling this super bug before it adapts in our healthcare facilities. Furthermore, more intensive efforts are required, and one such crucial step is the support from funding agencies to initiate multidisciplinary research to better understand its ecology, evolution, and resistance mechanisms, which will go a long way for its treatment and prevention.
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            Vertebrate endothermy restricts most fungi as potential pathogens.

            The paucity of fungal diseases in mammals relative to insects, amphibians, and plants is puzzling. We analyzed the thermal tolerance of 4802 fungal strains from 144 genera and found that most cannot grow at mammalian temperatures. Fungi from insects and mammals had greater thermal tolerances than did isolates from soils and plants. Every 1 degrees C increase in the 30 degrees C-40 degrees C range excluded an additional 6% of fungal isolates, implying that fever could significantly increase the thermal exclusion zone. Mammalian endothermy and homeothermy are potent nonspecific defenses against most fungi that could have provided a strong evolutionary survival advantage against fungal diseases.
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              Fungi and the Rise of Mammals

              The Mammalian Lifestyle Is Energetically Costly Here are two indisputable facts: we are living in the age of mammals [1], and immunologically intact mammals are highly resistant to fungal diseases, such that most human systemic fungal are considered “opportunistic” [2]. Could these two facts be connected? The mammalian lifestyle is characterized by endothermy, homeothermy, and care for the young, including nourishment via lactation, all of which are energetically costly activities. In contrast, reptiles, which are ectotherms, require about one-tenth of the daily mammalian energy needs [3], and reptilian development is faster and requires less parental involvement. Given this energy handicap, how did mammals replace reptiles as the dominant land animals? This essay further develops the hypothesis originally proposed seven years ago that fungi contributed to the emergence of mammals by creating a fungal filter at the end of the Cretaceous that selected for the mammalian lifestyle and against reptiles [4]. Mammals Are Naturally Resistant to Fungal Diseases Mammals are highly resistant to systemic fungal diseases. Whereas dermatophyte-associated diseases are common, these are seldom life threatening. For humans most fungal diseases were described in the 20th century and are associated with changes in the host such as iatrogenic immunosuppression, antibiotic-mediated disruption of the microflora, or other immune-impairing conditions as HIV infection, hematologic malignancies, and rheumatologic conditions. Unlike viral and bacterial diseases human mycoses are seldom contagious. Endothermy and homeothermy are thought to contribute to mammalian resistance to mycosis by creating a thermal exclusionary zone that inhibits most fungal species [5]. The remarkable resistance of mammals to mycotic diseases is probably a combination of a vertebrate immune system, with both innate and adaptive arms, and elevated body temperatures. Experimental evidence for the synergy of temperature and immunity is apparent from studies of cryptococcal infection in rabbits, which have core temperatures of 40–41°C [6]. Rabbits are naturally resistant to systemic C. neoformans infection. However, rabbits can be infected with C. neoformans when inoculated in the skin or cornea, which are cooler, but the fungus does not disseminate. However, when rabbits are immunosuppressed with corticosteroids, C. neoformans infection is rapidly fatal [7]. Primitive mammals like the platypus, with core temperatures near 32°C, are susceptible to Mucor amphibiorum, a fungus with a maximal thermal tolerance of 36°C that would make it avirulent for higher mammals [8]. The resistance of mammals to fungal diseases is in sharp contrast to the vulnerability of other vertebrates, such as amphibians, a group that is currently under severe pressure from a chrytrid [9]. Like mammals, amphibians have adaptive immunity, but unlike mammals, they are ectotherms and lack a thermal environment that is exclusionary to fungi. Hence, their vulnerability to fungal diseases echoes the experimental findings in rabbits whereby high resistance is conferred by a combination of high temperature and vertebrate-level immunity [6]. Amphibians can be cured of chrytridomycosis if placed at 37°C [10]. Another example of the protection provided by the combination of vertebrate-level immunity and endothermy comes from bats. In the summer bats manifest high activity and mammalian temperatures, but during winter hibernation their core temperatures drop as they hibernate and become vulnerable to infection with Geomyces destructans, a fungus that is decimating several North American bat species [11]. Infected bats woken from hibernation made full recovery when provided with supportive care, as higher body temperature inhibited fungal growth [12]. It is noteworthy that birds, which are also endotherms, are susceptible to Aspergillus fumigatus [13], a thermotolerant fungus that can survive up to 55°C [14]. A computation of the optimal temperature that would provide maximal protection against fungi given the caloric needs needed to maintain elevated temperatures yielded a value of 36.7°C, which is very close to mammalian temperatures [13]. This raises the possibility that mammalian resistance to fungi through the combination of vertebrate-level immunity and endothermy could have been the result of selection by pathogenic fungi. A Fungal Filter at the Cretaceous-Tertiary (K-T) Boundary Mammals replaced reptiles as the dominant land forms after the catastrophe that marked the end of the Cretaceous and the beginning of the Tertiary, an event known as the K-T boundary. The currently favored hypothesis for the demise of dinosaurs and end of the age of reptiles is a bolide impact approximately 65 million year ago with the possibility that other events, such as increased volcanism, contributed to disrupting the cretaceous ecosystem [15]. That ecological calamity was accompanied by massive deforestation [16], an event followed by a fungal bloom [17], as the earth became a massive compost. Although one cannot know which spores were present at the time, the likelihood that pathogenic fungi existed at the K-T boundary is enhanced by the finding that the potential for pathogenicity probably arose independently several times in evolution [18]. There is now increasing evidence that large dinosaurs were warm bodied [19], as a result of their size, which would have entailed considerable heat generation dependent on food metabolism and their metabolic activities. Large animals at the top of the food chain, such as dinosaurs, are highly vulnerable to ecosystem disruption. The altered ecosystem would have implied disruption of food sources and changed climate, which is thought to have included a significant cooling of the earth [20], by dust clouds and fires. Such stresses would be expected to weaken any survivors of the bolide blast with consequent immunological impairment and could have made survivors, and their eggs, susceptible to fungal diseases, especially if they could not maintain body warmth in the setting of starvation. Since there are reptiles today, it is clear that some reptiles survived the K-T boundary cataclysm. This raises the question, if reptiles were previously so successful, why did they not reclaim the earth to launch a second reptilian age? It is difficult to imagine how mammals could have replaced reptiles as the dominant land forms without some selection mechanism for this energetically costly lifestyle. This led me to propose the hypothesis that fungal proliferation after the devastation of the KT event preferentially selected for the fungal-resistant endothermic and hindered the re-emergence of a second reptilian age [4]. Although we do not know the timeline for the recovery of the planet climate, it is estimated that photosynthesis was shut down for 6 months and climate cooling persisted for at least 9 years [20], and the occurrence of a fungal bloom sufficient to have left fossil evidence implies that surviving animals were exposed to massive numbers of fungal spores. The darkened skies and cooler temperatures that accompanied the K-T cataclysm [20] would have shielded the sun and reduced the ability of ectothermic creatures such as reptiles to induce fevers by insolation, a necessary activity for protection against fungal diseases. Hence, it is reasonable to posit that ectothermic creatures unable to induce behavioral fevers and in weakened states from environmental stress would have been at a severe disadvantage relative to small mammals with their innate thermal exclusionary zones for fungal growth. Further complicating the situation for reptiles is that eggs can be vulnerable to fungal attack [21], whereas mammalian progeny would be protected in placentae. Climate Change and Future Fungal Threats Climate warming implies that the temperate gradient from mammals and average environmental temperatures will be reduced. Higher global temperatures could select for more thermally tolerant fungi, and it is possible that many fungi with current pathogenic potential for mammals that are unable to cause disease in mammals due to thermal intolerance will acquire the capacity to survive at mammalian temperatures and thus become pathogenic for mammals [22]. This concern is heightened by the fact that some fungi can be easily adapted to higher temperatures by thermal selection, as exemplified by the generation of a thermally resistant entopathogenic fungus as an attempt to create a pest control strain that would be less susceptible to insect-induced behavioral fevers [23]. The Fungal-Mammalian Emergence Hypothesis in Context The fungal-mammalian emergence hypothesis posits that fungi selected for the emergence of mammals. The hypothesis suggests an explanation for how the highly energy-intensive mammalian lifestyle was selected and for the relative resistance of immunologically intact mammals to fungal diseases. The hypothesis is a plausible synthesis assembled from very disparate lines of evidence. At this time it is unlikely that experimental evidence will be available in the near future to validate or refute this hypothesis simply by the very nature of what it tries to explain, and the remoteness of past events. For example, given that the animals that died as a result of the KT-related events represent an extremely small part of the fossil record, it is unrealistic to imagine finding fossils that could unequivocally be dated to the time in question with evidence of fungal disease. Fungal diseases can leave traces in the fossil record, as manifested by the finding of Coccidioides-like spherules in a fossil bison from the Holocene [24], but those fossils are very recent relative to the KT event and fungal effects on bone tissue usually reflect chronic infections. In contrast, fungal diseases caused by microscopic organisms that killed hosts by destroying soft tissues would leave no fossil record. On the other hand, recent developments with amphibian chrytridmycosis and the white nose syndrome in bats provide strong circumstantial evidence for the notion that fungal diseases could have provided strong selection pressures and driven some species to extinction. Although these are examples of individual fungal-host interaction in specialized ecological settings, they do provide precedents for the notion that fungi can be powerful selective forces for vertebrate species. In addition, there is now considerable evidence that fungi are potential threats to entire ecosystems [25]. The fungal-mammalian emergence hypothesis will likely continue to evolve as new information is available and is best considered as a cognitive tool for stimulating thinking and discussion on global issues related to evolutionary selection, infectious diseases, and ecological change.
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                Author and article information

                Journal
                Health Secur
                Health Secur
                hs
                Health Security
                Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                2326-5094
                2326-5108
                01 August 2017
                01 August 2017
                01 August 2017
                : 15
                : 4
                : 341-342
                Author notes
                Arturo Casadevall, MD, Chair, Molecular Microbiology & Immunology, Johns Hopkins Bloomberg School of Public Health 615 N. Wolfe Street, Baltimore, MD 21205, Email: acasade1@ 123456jhu.edu
                Article
                10.1089/hs.2017.0048
                10.1089/hs.2017.0048
                5576259
                28742386
                © Arturo Casadevall, 2017; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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                References: 6, Pages: 2
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                Special Feature: Global Catastrophic Biological Risks

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