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International Journal of Microbiology
Volume 2012 (2012), Article ID 363764, 12 pages
http://dx.doi.org/10.1155/2012/363764
Review Article

Hosting Infection: Experimental Models to Assay Candida Virulence

Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK

Received 1 August 2011; Accepted 13 October 2011

Academic Editor: Arianna Tavanti

Copyright © 2012 Donna M. MacCallum. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Although normally commensals in humans, Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, and Candida krusei are capable of causing opportunistic infections in individuals with altered physiological and/or immunological responses. These fungal species are linked with a variety of infections, including oral, vaginal, gastrointestinal, and systemic infections, with C. albicans the major cause of infection. To assess the ability of different Candida species and strains to cause infection and disease requires the use of experimental infection models. This paper discusses the mucosal and systemic models of infection available to assay Candida virulence and gives examples of some of the knowledge that has been gained to date from these models.

1. Candida and Man

1.1. Carriage of Candida Species

In healthy individuals Candida species are harmless members of the normal gastrointestinal (GI), oral, and vaginal microbial flora. It is assumed that everyone carries Candida in their GI tract (reviewed in [1]), with C. albicans the species most frequently identified in faecal sampling, representing 40–70% of isolates [24]. Other isolates are usually identified as C. parapsilosis, C. glabrata, C. tropicalis, or C. krusei [24].

In comparison to GI carriage, oral carriage is observed in only ~40% of healthy individuals, with considerable variation found between studies (reviewed in [1]). Higher carriage levels are generally associated with diabetes, cancer, HIV, or denture use (reviewed in [1]). Again, the majority of isolates (~80%) are identified as C. albicans, with C. glabrata or C. parapsilosis making up the remainder [59].

Vaginal carriage occurs in an even smaller proportion of the healthy population, with only ~20% of healthy women found to have vaginal Candida carriage [1013]. C. albicans is again the most commonly identified species, with C. glabrata the only other species usually found [10, 12, 1417].

Therefore, C. albicans is the major species found as a commensal in healthy individuals, with four other species, C. tropicalis, C. parapsilosis, C. glabrata, and C. krusei, also found.

1.2. Candida and Disease

Candida species, however, have an alternative lifestyle, causing opportunistic infection in hosts with altered physiological or immune response. The infections caused by Candida species range from self-limiting, superficial mucosal lesions (commonly referred to as thrush), chronic and/or recurrent mucosal, skin, and nail infections, through to life-threatening invasive or disseminated infection [1, 1821].

In humans, the most common infections caused by Candida species are superficial infections of the mucosa, skin, and nails [2024]. Pseudomembranous oral thrush is common in babies and in the elderly, but is also found in HIV-positive individuals and cancer patients (reviewed in [1, 25]). Denture stomatitis is also a significant infection, occurring in approximately 60% of denture wearers [26, 27]. In oral candidiasis most infections are caused by C. albicans (58%), with the remainder caused by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei [28, 29].

Vaginal candidiasis, or thrush, another form of superficial infection, affects approximately 75% of women of child-bearing age [30, 31]. C. albicans is most commonly isolated, with C. glabrata also found, but at a lower frequency [17, 30, 3235], reflecting the species normally carried in the vulvovaginal area.

An additional form of candidiasis involving the mucous membranes, as well as the skin and nails, is chronic mucocutaneous candidiasis. Unlike other forms of candidiasis, there is evidence that this condition can be inherited or is associated with thymoma, with almost every infection caused by C. albicans [2024, 36].

The most serious infections caused by Candida species, however, are invasive or disseminated infections. Candida species cause ~11% of all bloodstream infections and 20% of those occurring in the ICU population [3739]. However, in comparison to bacterial infections occurring in the same patient population, these infections are much more serious as mortality rates remain high (~45%) [1, 40]. This is due, in part, to diagnostic difficulties and limited antifungal therapies. Invasive infections occur in those patients who are already seriously ill, with major risk factors including admission to ICU, surgery (especially abdominal surgery), and neutropenia (reviewed in [1]). The five Candida species commonly isolated from the human GI tract are also responsible for 90% of invasive Candida infections [1, 41]. Geographical variations in the epidemiology of these infections do occur, with C. tropicalis the most common cause of invasive Candida infection in both India and Singapore [4244]. In addition, in patients with haematological malignancies and in young children and babies, there is increased incidence of C. tropicalis and C. parapsilosis [4549].

Patients with invasive Candida infection usually present with clinical symptoms similar to those associated with invasive bacterial infection and can eventually develop sepsis [50]. From autopsy reports, it is evident that the lungs and the kidneys are the organs most commonly affected, with fungal lesions also found in the heart, liver, and spleen [5155]. Infection most likely originates from the GI tract, as the majority of invasive infections show GI involvement (oesophagus, stomach, and intestines) [51, 53] and Candida isolates from the bloodstream are identical, or closely related, to isolates from nonsterile sites of the same patient [56].

Increasing numbers of patients suffering immunosuppression and undergoing invasive treatments, for example, for cancers and organ transplants, mean that there is an ever-increasing population at risk of invasive fungal infection. With a medical need for the development of new and more efficient diagnostics and therapies for fungal infection, we need a better understanding of Candida pathogenesis, that is, how do the major Candida species cause opportunistic infections?

2. Experimental Models of Candida Infection

Experimental infection models allow disease development to be followed from the moment that fungal cells are introduced into the host. To be a good model, a model should be reproducible, relatively easy to set up, and should reproduce the major clinical symptoms seen in the human disease. It is also an added advantage if the model is cost effective. Models which satisfy these conditions allow further in-depth investigation of Candida virulence to be carried out and, subsequently, allow inferences about Candida virulence in human disease to be made.

Although a great deal of preliminary research on virulence can be carried out by laboratory experiment, infection modelling requires the involvement of a host organism. It is only in a whole organism that the complex host-fungus interactions that determine whether or not disease will occur can be investigated. Although larger animals have been used to study Candida infections, for example, macaques [57, 58], piglets [59], rabbits [6062], and guinea pigs [63, 64], the majority of Candida virulence studies use rodent infection models. This is due to economic factors, ease of handling, and the availability of genetically modified mouse strains, which allow human genetic conditions to be mimicked.

In this paper, experimental animal models that have been developed for Candida virulence assays are discussed. It should be noted that the majority of models focus on C. albicans as this is the major species associated with human Candida infections.

2.1. Mucosal Infection Models

To model Candida oral and vaginal infections, mucosal models have been developed mainly in rats and mice. The procedures used in rats and mice are generally similar. However, the larger animal has the added advantage that denture-associated fungal biofilms formation can also be studied in a host [65]. Establishment of infection at mucosal sites generally requires treatment with immunosuppressive agents, oestrogen, or antibiotics prior to infection, or the use of germ-free animals [6668]. However, the nude (Foxn1nu) mouse model of oral infection allows infection to be established without any immunosuppression or other pretreatment [69]. Greater detail can be found in more extensive reviews of these infection models [67, 68, 70, 71].

In order to assess virulence in mice using the oral infection model, mice are routinely pretreated with corticosteroids and Candida cells are administered into the oral cavity of anaesthetised animals either by applying a Candida-soaked cotton bud under the tongue or by applying the inoculum directly onto the teeth, gums, and oral cavity [67, 70, 72]. Virulence in this model is usually determined by fungal organ burden and histopathology.

Both rat and mouse models have been used to compare the virulence of C. albicans mutant strains and also clinical isolates [7377]. Using these models, C. albicans mutant strains which are unable to switch between the yeast and hyphal growth forms were found to be unable to cause oral infection, demonstrating a requirement for yeast-hypha switching in oral infection [75]. In addition, protein kinase Ck2 was also shown to be required for oropharyngeal C. albicans infections [77].

Mouse and rat models have also been developed to assay Candida virulence in vaginal infection. In these models the rodents are maintained in oestrus in order to maintain colonisation and infection, which probably mimics pregnancy-associated candidiasis [7881]. In rats, this generally involves surgery to remove the ovaries, with subsequent administration of oestrogen [81]. Recently, however, a new rat model has been developed, similar to the mouse model, where oestrus is maintained merely through administration of oestrogen [82], which will increase the ease of setting up the infection model. Immunosuppression of the host can also prolong colonisation by Candida species [83]. These models allow us to examine single vaginitis episodes; however, a satisfactory model of recurrent, chronic vaginitis is not yet available.

The virulence of C. albicans clinical isolates has been compared in rodent vaginitis models, demonstrating that isolates have varying capacities to cause disease [84, 85]. This model has also been used to assess virulence of genetically modified C. albicans mutants [8587].

In addition to assessing C. albicans virulence, this model can be used to examine virulence of other Candida species. As C. glabrata is also associated with human vaginal infection, researchers have used the rat vaginitis model to evaluate the virulence of a C. glabrata petite mutant, discovering than the mutant was more virulent that the parental strain [88]. In addition, C. parapsilosis isolates have also been assessed for their ability to cause vaginal infection in the rat model [80]. In this study only a single isolate, recently obtained from a woman with active vaginal infection, was capable of initiating infection [80].

A major development in Candida virulence testing at mucosal surfaces occurred recently with the development of a concurrent oral and vaginal infection model by Rahman et al. [72]. This mouse model allows both oral and vaginal infections to be initiated in the same host, greatly reducing the numbers of animals required for these virulence assays. A comparison of the virulence of three different C. albicans isolates in this model clearly demonstrated that C. albicans isolates were not equally virulent, with obvious differences in their ability to initiate mucosal infections [72].

2.2. Invasive Infection Models

Mouse models of invasive fungal infection have been the most popular methods to assess Candida virulence up until the present day, although assays have also been carried out in rabbits, guinea pigs, and rats also used in some studies. There are two major models of Candida invasive infection, the intravenous (IV) challenge model and the gastrointestinal (GI) colonisation with subsequent dissemination model. These models were recently reviewed [89].

2.2.1. Intravenous Challenge Model

The mouse IV challenge model has been used to study Candida virulence since the 1960s and is both well characterised and reproducible [9092]. Candida cells are injected directly into the lateral tail vein, bypassing any requirement of the fungus to cross epithelial and endothelial barriers to gain entry into the bloodstream. In this mouse model, which is similar to human invasive infection occurring with catheter involvement, fungal cells are found in all organs, but disease progresses only in the kidneys and brain, which depends upon inoculum level and mouse strain [9193]. Sepsis develops as invasive disease progresses, which eventually leads to the death of the mouse [92, 94, 95].

In these models of Candida invasive infection, virulence is determined by monitoring survival of infected mice and/or by quantifying fungal organ burdens at predetermined times after infection. Drug treatments can also be administered to the host to allow host conditions to be mimicked, for example, immunosuppression [88, 96110] or diabetes [99], with greater Candida virulence in both of these treatments.

Using immunocompetent mice, the IV challenge model has been used to compare the virulence of different Candida species [9799, 107, 111114]. C. albicans is clearly the most virulent species [97, 98, 111, 112, 114], followed closely by C. tropicalis [97, 98, 111, 112, 114]. In contrast, C. krusei and C. parapsilosis were unable to kill the infected animals, even at high inoculum levels, and fungi were eventually cleared from the host [98, 111, 114].

In immunosuppressed mice, C. tropicalis showed greater virulence, with disease progressing in the kidneys, rather than infection being controlled which occurs in immunocompetent mice [96, 98, 99, 107, 115]. C. parapsilosis and C. krusei remained unable to initiate progressive infections, even with addition of immunosuppressive treatments [98, 107], although administration of a very high inoculum potentially allows some C. parapsilosis isolates to initiate disease [108, 110].

Within each Candida species, clinical isolates were found to show considerable virulence differences in the IV challenge model. This was true for C. albicans [97, 107, 116, 117], C. tropicalis [97, 99, 112, 115, 118], and C. parapsilosis [108, 119], with some isolates unable to initiate invasive infections. This raises questions as to whether virulence results found for a single strain or isolate are representative of the entire species. This could be of particular importance for C. albicans studies where the vast majority of gene disruption studies have been carried out in a single strain, SC5314, background.

Numerous studies have evaluated C. tropicalis clinical isolate virulence differences; however, there are very few studies published on the virulence of genetically modified C. tropicalis strains. One study which has been published was able to demonstrate that a secreted acid protease was required for full virulence of C. tropicalis in immunocompetent mice [120]. In contrast to C. tropicalis, vast numbers of studies have been published on the virulence of C. albicans mutants, with over 200 genes identified as contributing to the C. albicans virulence in this model (reviewed in [89]).

C. glabrata behaves very differently from the other Candida species in the mouse model of invasive infection. Although C. glabrata is maintained, or tolerated, at high levels in the kidneys of immunocompetent mice, the mice did not die and there was little inflammation associated with the fungal cells [113, 114]. Immunosuppression appears to increase virulence of C. glabrata in terms of higher fungal organ burdens, but mouse survival is only increased in some C. glabrata infections [100, 103106]. However, because immunosuppression may allow invasive disease to develop in C. glabrata-infected mice, these treatments have been added to an infection model used in some studies to compare the virulence of genetically modified C. glabrata, with fungal burdens used as the virulence estimate [88, 101, 102, 105]. The immunosuppressed mouse infection model has demonstrated the importance of hypertonic stress responses, the cell wall integrity pathway, and nitrogen starvation responses in C. glabrata virulence [103, 104, 106]. In addition, this model has identified a petite mutant, strains expressing hyperactive alleles of the transcription factor gene PDR1 and the ace2 null mutant as being more virulent than their parent strains [88, 105, 121]. However, it should be noted that the hypervirulent phenotype of the C. glabrata ace2 null was completely lost in immunocompetent mice [122]. In other virulence experiments in immunocompetent mice, where virulence was determined from fungal organ burdens at day 7 after infection, researchers were able to demonstrate that the cell wall integrity pathway [123, 124] and oxidative stress response [125], as well as the transcription factor Pdr1p and some of the genes that it regulates [101, 121], contribute to C. glabrata virulence.

2.2.2. Gastrointestinal Colonisation and Dissemination Model

Gastrointestinal models can either be set up in neonatal or adult mice. Intragastric infection of neonatal mice leads to persistent colonisation, without any requirement for pretreatment of the mice. However, to obtain colonisation of adult mice, the natural mouse gastrointestinal flora must first be removed by treatment with broad spectrum antibiotics. Adult mice can either be infected by gavage (intragastrically) or orally via their chow or drinking water. Subsequent treatment of Candida colonised mice with immunosuppressants and/or drugs which damage the gut wall allow fungal dissemination to occur (reviewed in [70, 126]).

In the gastrointestinal models fungal colonisation is highest in the stomach, caecum, and small intestine [107, 127129], reflecting some of the clinical findings seen in human invasive infection. During the model, persistent colonisation is routinely monitored by noninvasive faecal fungal counts, and after dissemination Candida cells can be cultured from the liver, kidneys, and spleen [128130]. However, differences may be seen between mouse strains [131].

This murine model is believed to be a more accurate reflection of the events occurring in the human patient, with broad spectrum antibiotics allowing fungal overgrowth and later invasive therapies causing mucosal damage. Mucosal damage then allows Candida to enter the bloodstream and disseminate to the internal organs. In the mouse, similar to human patients, there is increased animal-to-animal variation compared to the intravenous challenge model, requiring higher numbers of animals per group to obtain statistically significant results [128130].

Comparison of Candida species virulence in this model demonstrated that C. parapsilosis had lower virulence compared to C. albicans and C. tropicalis, as there was little evidence of dissemination from the gut [107, 132]. However, C. parapsilosis was successful in establishing persistent colonisation of the GI tract [107]. In separate studies, C. tropicalis appeared to be more virulent than C. albicans in the gastrointestinal model, with greater dissemination to the internal organs [133, 134] and higher mortality rates [97, 134]. However, given the levels of variation observed in other models for the virulence of strains of different Candida species, further isolates will require to be assayed before a definitive conclusion on the relative virulence of the two species can be made.

To date, only a limited number of C. albicans mutant strains have been tested in the gastrointestinal colonisation and dissemination infection model, with only 6 mutants identified so far as contributing to virulence [89, 135]. However, this model has demonstrated that a constitutively filamentous C. albicans mutant was unable to disseminate, suggesting that the ability to switch between morphological forms may be more important for dissemination [136].

C. glabrata also behaved differently from the other four major Candida species in this model, being unable to colonise the oesophageal tissue in the neonatal mouse gastrointestinal colonisation and dissemination model [137]. Again, there was little host inflammatory response to C. glabrata [137], suggesting that C. glabrata virulence mechanisms may be quite different from those of the other species studied.

3. Beyond the Genome: Challenges of Candida Virulence Testing in the Postgenomic Era

The genome sequences of C. albicans, C. glabrata, C. tropicalis, and C. parapsilosis are now available [138, 139], encouraging the creation of large-scale mutant libraries. The challenge comes, however, when these large libraries are to be screened for genes involved in fungal virulence, with logistical, financial, and ethical issues to be considered.

In library screening programmes carried out to date different virulence testing strategies have been taken. Noble et al. [140] used signature-tagged mutagenesis to allow pools of mutants to be assayed in small numbers of animals, significantly reducing the animal numbers required for testing. By contrast, in order to screen a library of 177 C. albicans strains for altered virulence, Becker et al. [141] assayed each strain in 15 mice. From these two examples it is clear that traditional testing methods can lead to large numbers of mice being required to assay virulence. However, researchers have recently begun to address the issues of virulence testing large numbers of Candida strains by developing a range of minihosts, which are mainly based on invertebrate hosts.

Minihosts may not initially appear relevant to the human disease, but these hosts do possess an innate immune system and this is known to be critical in the development of Candida infections [142]. However, many of the minihosts do not possess an adaptive immune system, which may limit their usefulness. In addition, the majority of invertebrate models have the disadvantage that they must be kept at temperatures below normal human body temperature, with the exception of Galleria which can be incubated at 37°C. Potentially, incubation at lower temperatures may induce physiological changes in the fungus, affecting host-fungus interactions during disease development.

3.1. Wax Moth and Silk Worm Larval Models

The first minihost model developed for Candida virulence testing was the Galleria mellonella (wax moth) larval model [143]. In this model fungi are injected into larvae, via a proleg, and survival is monitored over a short time period. The model is relatively cheap and has the added advantage that large numbers of larvae can be infected with each mutant strain, increasing the statistical power of the assay. The Galleria model has been successfully used to model C. albicans virulence, with results roughly similar to those found in mouse infection models [143146]. A similar model has also been developed using the silk worm (Bombyx mori) [147, 148]. Both C. albicans and C. tropicalis are capable of killing silk worm larvae within two days [148], and C. albicans virulence differences were shown to correlate with results previously found in a mouse model [147].

3.2. Drosophila melanogaster

The fruit fly, Drosophila melanogaster, has also been used to assay Candida virulence [149152]. The susceptibility of wild-type D. melanogaster continues to be debated; however, both Toll- and Spätzle-deficient fruit flies are susceptible to infection by Candida species when fungi are injected directly into the thorax [149151]. Again, D. melanogaster models also have the advantage that large numbers of flies (>30 flies) can be infected with each Candida strain, increasing the statistical power of the assay.

In fruit flies, C. albicans was shown to be more virulent than other Candida species, confirming the results found in mammalian models (see above; [149]). In addition, virulence results for C. albicans clinical isolates and mutants were broadly similar to those found in the mouse systemic model [149151]. However, differences do occur. In the fruit fly, CO2 sensing is important for virulence, but this was not the case in the mouse IV challenge model [153]. This model has already been successfully used to screen a C. albicans mutant library, identifying Cas5, a transcription factor involved in cell wall integrity, as being required for full virulence [154].

In addition to the systemic D. melanogaster infection model, a new gastrointestinal infection model has also been developed recently, which should provide new options for virulence screening in a gastrointestinal model [152].

3.3. Caenorhabditis elegans

In addition to fly and larval models, the nematode Caenorhabditis elegans has also been evaluated as an infection model for assaying Candida virulence [155]. This model is particularly suited to high-throughput screening, as the Candida cells are fed to the nematodes in their food and assays are carried out in multi-well plates. This model has also been used successfully to screen a C. albicans transcription factor mutant library, allowing identification of transcription factor genes involved in hypha formation [155].

3.4. A Vertebrate Minihost: Zebrafish (Danio rerio)

Zebrafish are the first vertebrate minihost model developed for virulence testing of Candida. This organism has the added advantage of having both innate and adaptive immune systems [156], and methods are also available to allow fish gene expression to be manipulated to mimic human genetic conditions [157].

The first virulence assay developed in zebrafish involved intraperitoneal injection of C. albicans into 7-month-old zebrafish [158]. In this model, similar to mouse models, progressive infection depends upon dose and is associated with increased proinflammatory gene expression. This model also allows increased group sizes, with group sizes of 20 fish being used to date. Using this model, researchers demonstrated that a clinical isolate with reduced virulence in a mouse model also showed reduced virulence in this model [158]. In addition, a C. albicans mutant (efg1/cph1) known to have attenuated virulence due to filamentation defects also had reduced virulence in this model [159, 160]. Of greater interest was the finding that, although these mutants were unable to form filaments in vitro, they clearly formed filaments when growing within fish. This model also allows interactions between zebrafish immune cells and Candida cells to be imaged, which will be made even easier in the future with the development of the new transparent adult (casper) zebrafish [161].

A second zebrafish infection model has also been described, where each fish larva (36 h after fertilization) is infected directly into the hindbrain ventricle with approximately 10 fungal cells [162]. In this model the C. albicans efg1/cph1 mutant again demonstrated attenuated virulence, similar to results found in the mouse IV challenge model [162].

There are, however, disadvantages to the zebrafish infection models. One of the major drawbacks of this model, in common with the majority of other minihosts, is that the fish need to be kept at 28-29°C, which does not allow accurate mimicking of human infection.

4. Assaying Virulence in Experimental Models: Final Considerations

There are some important points to remember when evaluating Candida virulence in experimental infections. The first concerns the Candida species of interest. Although C. albicans, C. tropicalis, C. glabrata, and C. krusei are all associated with human carriage and infection, they are not natural mouse commensals or pathogens [163]. As such, there may be different interactions occurring between the fungus and the two different host species. This is of particular relevance when considering C. glabrata and its inability to initiate disseminated infection in the IV challenge models, especially when we know that C. glabrata can cause lethal infections in severely ill humans [164].

The second point to consider is that, although the immune systems of mice and men are similar, there are differences that could affect how the host and fungus interact [165168]. Of particular relevance to Candida infections are differences in proportions of neutrophils and lymphocytes in the blood, complement receptor expression, and T-cell differentiation, to name but a few (reviewed in [168]). In addition, different mouse strains show differing susceptibility to infection, which could potentially alter virulence results [93, 169172].

The third point to consider is which model should be used to evaluate Candida virulence. Some C. albicans isolates exhibit virulence differences depending upon the infection model being used [72, 134, 173]. A good example is the C. albicans genome sequenced strain SC5314. In the IV challenge model, SC5314 is one of the most virulent C. albicans isolates, causing lethal infection in a relatively short time [92, 116]; however, in a vaginal infection model, SC5314 is a very poor coloniser of the vaginal mucosa [72]. In addition, a nongerminative C. albicans strain [173] and a ura3 minus C. albicans strain [174], both of which were attenuated in systemic infection models [173, 175177], successfully established mucosal infections [173, 174].

Only careful consideration of the above points will allow the Candida researcher to select the appropriate experimental Candida infection model to answer a particular research question. These models remain essential for increasing our understanding of fungal pathogenesis since both fungal attributes and host responses are known to contribute to the development of clinical disease.

Acknowledgment

The author would like to apologise to those whose work could not be included in this review due to lack of space.

References

  1. D. M. MacCallum, “Candida infections and modelling disease,” in Pathogenic Yeasts, The Yeast Handbook, H. R. Ashbee and E. Bignell, Eds., pp. 41–67, Springer, 2010. View at Google Scholar
  2. M. E. Bougnoux, D. Diogo, N. François et al., “Multilocus sequence typing reveals intrafamilial transmission and microevolutions of Candida albicans isolates from the human digestive tract,” Journal of Clinical Microbiology, vol. 44, no. 5, pp. 1810–1820, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. S. Kusne, D. Tobin, A. W. Pasculle, D. H. Van Thiel, M. Ho, and T. E. Starzl, “Candida carriage in the alimentary tract of liver transplant candidates,” Transplantation, vol. 57, no. 3, pp. 398–402, 1994. View at Google Scholar · View at Scopus
  4. P. D. Scanlan and J. R. Marchesi, “Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces,” ISME Journal, vol. 2, no. 12, pp. 1183–1193, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. M. Belazi, A. Velegraki, A. Fleva et al., “Candidal overgrowth in diabetic patients: potential predisposing factors,” Mycoses, vol. 48, no. 3, pp. 192–196, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. H. Ben-Aryeh, E. Blumfield, R. Szargel, D. Laufer, and I. Berdicevsky, “Oral Candida carriage and blood group antigen secretor status,” Mycoses, vol. 38, no. 9-10, pp. 355–358, 1995. View at Google Scholar · View at Scopus
  7. G. Campisi, G. Pizzo, M. E. Milici, S. Mancuso, and V. Margiotta, “Candidal carriage in the oral cavity of human immunodeficiency virus-infected subjects,” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, vol. 93, no. 3, pp. 281–286, 2002. View at Publisher · View at Google Scholar
  8. S. Thaweboon, B. Thaweboon, T. Srithavaj, and S. Choonharuangdej, “Oral colonization of Candida species in patients receiving radiotherapy in the head and neck area,” Quintessence International, vol. 39, no. 2, pp. e52–57, 2008. View at Google Scholar · View at Scopus
  9. J. Wang, T. Ohshima, U. Yasunari et al., “The carriage of Candida species on the dorsal surface of the tongue: the correlation with the dental, periodontal and prosthetic status in elderly subjects,” Gerodontology, vol. 23, no. 3, pp. 157–163, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. M. Dan, R. Segal, V. Marder, and A. Leibovitz, “Candida colonization of the vagina in elderly residents of a long-term-care hospital,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 25, no. 6, pp. 394–396, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. I. W. Fong, “The rectal carriage of yeast in patients with vaginal candidiasis,” Clinical and Investigative Medicine, vol. 17, no. 5, pp. 426–431, 1994. View at Google Scholar · View at Scopus
  12. M. V. Pirotta and S. M. Garland, “Genital Candida species detected in samples from women in Melbourne, Australia, before and after treatment with antibiotics,” Journal of Clinical Microbiology, vol. 44, no. 9, pp. 3213–3217, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. E. Rylander, A. L. Berglund, C. Krassny, and B. Petrini, “Vulvovaginal Candida in a young sexually active population: prevalence and association with oro-genital sex and frequent pain at intercourse,” Sexually Transmitted Infections, vol. 80, no. 1, pp. 54–57, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. E. M. de Leon, S. J. Jacober, J. D. Sobel, and B. Foxman, “Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes,” BMC Infectious Diseases, vol. 2, article 1, 2002. View at Publisher · View at Google Scholar
  15. A. Beltrame, A. Matteelli, A. C. C. Carvalho et al., “Vaginal colonization with Candida spp. in human immunodeficiency virus - Infected women: a cohort study,” International Journal of STD and AIDS, vol. 17, no. 4, pp. 260–266, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. O. Grigoriou, S. Baka, E. Makrakis, D. Hassiakos, G. Kapparos, and E. Kouskouni, “Prevalence of clinical vaginal candidiasis in a university hospital and possible risk factors,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 126, no. 1, pp. 121–125, 2006. View at Publisher · View at Google Scholar · View at PubMed
  17. A. Paulitsch, W. Weger, G. Ginter-Hanselmayer, E. Marth, and W. Buzina, “A 5-year (2000–2004) epidemiological survey of Candida and non-Candida yeast species causing vulvovaginal candidiasis in Graz, Austria,” Mycoses, vol. 49, no. 6, pp. 471–475, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. F. C. Odds, Candida and Candidosis, Bailliere Tindall, London, UK, 1988.
  19. B. Havlickova, V. A. Czaika, and M. Friedrich, “Epidemiological trends in skin mycoses worldwide,” Mycoses, vol. 51, supplement 4, pp. 2–15, 2008. View at Publisher · View at Google Scholar · View at Scopus
  20. C. H. Kirkpatrick and H. R. Hill, “Chronic mucocutaneous candidiasis,” Pediatric Infectious Disease Journal, vol. 20, no. 2, pp. 197–206, 2001. View at Publisher · View at Google Scholar
  21. C. H. Kirkpatrick, “Chronic mucocutaneous candidiasis,” European Journal of Clinical Microbiology and Infectious Diseases, vol. 8, no. 5, pp. 448–456, 1989. View at Google Scholar · View at Scopus
  22. A. Puel, C. Picard, S. Cypowyj, D. Lilic, L. Abel, and J. L. Casanova, “Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?” Current Opinion in Immunology, vol. 22, no. 4, pp. 467–474, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. K. Kisand, D. Lilic, J. L. Casanova, P. Peterson, A. Meager, and N. Willcox, “Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications,” European Journal of Immunology, vol. 41, no. 6, pp. 1517–1527, 2011. View at Publisher · View at Google Scholar · View at PubMed
  24. A. Puel, S. Cypowyj, J. Bustamante et al., “Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity,” Science, vol. 332, no. 6025, pp. 65–68, 2011. View at Publisher · View at Google Scholar · View at PubMed
  25. M. D. Richardson and D. W. Warnock, “Superficial candidosis,” in Fungal Infection: Diagnosis and Management, pp. 78–93, Blackwell Science, London, UK, 1997. View at Google Scholar
  26. T. Daniluk, G. Tokajuk, W. Stokowska et al., “Occurrence rate of oral Candida albicans in denture wearer patients,” Advances in Medical Sciences, vol. 51, pp. 77–80, 2006. View at Google Scholar · View at Scopus
  27. M. H. Figueiral, A. Azul, E. Pinto, P. A. Fonseca, F. M. Branco, and C. Scully, “Denture-related stomatitis: identification of aetiological and predisposing factors—a large cohort,” Journal of Oral Rehabilitation, vol. 34, no. 6, pp. 448–455, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. J. P. Lyon, S. C. da Costa, V. M. G. Totti, M. F. V. Munhoz, and M. A. De Resende, “Predisposing conditions for Candida spp. carriage in the oral cavity of denture wearers and individuals with natural teeth,” Canadian Journal of Microbiology, vol. 52, no. 5, pp. 462–467, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. R. H. Pires-Gonçalves, E. T. Miranda, L. C. Baeza, M. T. Matsumoto, J. E. Zaia, and M. J. S. Mendes-Giannini, “Genetic relatedness of commensal strains of Candida albicans carried in the oral cavity of patients' dental prosthesis users in Brazil,” Mycopathologia, vol. 164, no. 6, pp. 255–263, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. J. D. Sobel, “Vulvovaginal candidosis,” Lancet, vol. 369, no. 9577, pp. 1961–1971, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. J. D. Sobel, S. Faro, R. W. Force et al., “Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations,” American Journal of Obstetrics and Gynecology, vol. 178, no. 2, pp. 203–211, 1998. View at Publisher · View at Google Scholar · View at Scopus
  32. A. B. Guzel, M. Ilkit, T. Akar, R. Burgut, and S. C. Demir, “Evaluation of risk factors in patients with vulvovaginal candidiasis and the value of chromID Candida agar versus CHROMagar Candida for recovery and presumptive identification of vaginal yeast species,” Medical Mycology, vol. 49, no. 1, pp. 16–25, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. M. A. Kennedy and J. D. Sobel, “Vulvovaginal Candidiasis caused by non-albicans Candida species: new insights,” Current Infectious Disease Reports, vol. 12, no. 6, pp. 465–470, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. S. Asticcioli, L. Sacco, R. Daturi et al., “Trends in frequency and in vitro antifungal susceptibility patterns of Candida isolates from women attending the STD outpatients clinic of a tertiary care hospital in Northern Italy during the years 2002—2007,” New Microbiologica, vol. 32, no. 2, pp. 199–204, 2009. View at Google Scholar · View at Scopus
  35. S. Corsello, A. Spinillo, G. Osnengo et al., “An epidemiological survey of vulvovaginal candidiasis in Italy,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 110, no. 1, pp. 66–72, 2003. View at Publisher · View at Google Scholar
  36. F. L. van de Veerdonk, T. S. Plantinga, A. Hoischen et al., “STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis,” New England Journal of Medicine, vol. 365, no. 1, pp. 54–61, 2011. View at Publisher · View at Google Scholar · View at PubMed
  37. H. Markogiannakis, N. Pachylaki, E. Samara et al., “Infections in a surgical intensive care unit of a university hospital in Greece,” International Journal of Infectious Diseases, vol. 13, no. 2, pp. 145–153, 200. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. G. B. Orsi, L. Scorzolini, C. Franchi, V. Mondillo, G. Rosa, and M. Venditti, “Hospital-acquired infection surveillance in a neurosurgical intensive care unit,” Journal of Hospital Infection, vol. 64, no. 1, pp. 23–29, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. E. Sarvikivi, O. Lyytikäinen, M. Vaara, and H. Saxén, “Nosocomial bloodstream infections in children: an 8-year experience at a tertiary-care hospital in Finland,” Clinical Microbiology and Infection, vol. 14, no. 11, pp. 1072–1075, 2008. View at Publisher · View at Google Scholar · View at PubMed
  40. M. Morrell, V. J. Fraser, and M. H. Kollef, “Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality,” Antimicrobial Agents and Chemotherapy, vol. 49, no. 9, pp. 3640–3645, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. H. Wisplinghoff, H. Seifert, R. P. Wenzel, and M. B. Edmond, “Inflammatory response and clinical course of adult patients with nosocomial bloodstream infections caused by Candida spp,” Clinical Microbiology and Infection, vol. 12, no. 2, pp. 170–177, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. Y. A. L. Chai, Y. Wang, A. L. Khoo et al., “Predominance of Candida tropicalis bloodstream infections in a Singapore teaching hospital,” Medical Mycology, vol. 45, no. 5, pp. 435–439, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. S. Shivaprakasha, K. Radhakrishnan, and P. Karim, “Candida spp. other than Candida albicans: a major cause of fungaemia in a tertiary care centre,” Indian Journal of Medical Microbiology, vol. 25, no. 4, pp. 405–407, 2007. View at Google Scholar · View at Scopus
  44. I. Xess, N. Jain, F. Hasan, P. Mandal, and U. Banerjee, “Epidemiology of candidemia in a tertiary care centre of North India: 5-Year study,” Infection, vol. 35, no. 4, pp. 256–259, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. A. C. Pasqualotto, D. D. Rosa, L. R. Medeiros, and L. C. Severo, “Candidaemia and cancer: patients are not all the same,” BMC Infectious Diseases, pp. 50–56, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. R. Hachem, H. Hanna, D. Kontoyiannis, Y. Jiang, and I. Raad, “The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy,” Cancer, vol. 112, no. 11, pp. 2493–2499, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. E. Presterl, F. Daxböck, W. Graninger, and B. Willinger, “Changing pattern of candidaemia 2001-2006 and use of antifungal therapy at the University Hospital of Vienna, Austria,” Clinical Microbiology and Infection, vol. 13, no. 11, pp. 1072–1076, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. S. Vigouroux, O. Morin, P. Moreau, J. L. Harousseau, and N. Milpied, “Candidemia in patients with hematologic malignancies: analysis of 7 years' experience in a single center,” Haematologica, vol. 91, no. 5, pp. 717–718, 2006. View at Google Scholar · View at Scopus
  49. R. Saha, S. Das Das, A. Kumar, and I. R. Kaur, “Pattern of Candida isolates in hospitalized children,” Indian Journal of Pediatrics, vol. 75, no. 8, pp. 858–860, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. B. Spellberg and J. E. Edwards, “The pathophysiology and treatment of Candida Sepsis,” Current Infectious Disease Reports, vol. 4, no. 5, pp. 387–399, 2002. View at Google Scholar
  51. J. Berenguer, M. Buck, F. Witebsky, F. Stock, P. A. Pizzo, and T. J. Walsh, “Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis: disseminated versus single-organ infection,” Diagnostic Microbiology and Infectious Disease, vol. 17, no. 2, pp. 103–109, 1993. View at Publisher · View at Google Scholar · View at Scopus
  52. T. Lehrnbecher, C. Frank, K. Engels, S. Kriener, A. H. Groll, and D. Schwabe, “Trends in the postmortem epidemiology of invasive fungal infections at a university hospital,” Journal of Infection, vol. 61, no. 3, pp. 259–265, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. K. Donhuijsen, P. Petersen, and K. W. Schmid, “Trend reversal in the frequency of mycoses in hematological neoplasias: autopsy results from 1976 to 2005,” Deutsches Arzteblatt, vol. 105, no. 28-29, pp. 501–506, 2008. View at Publisher · View at Google Scholar · View at PubMed
  54. S. Antinori, M. Nebuloni, C. Magni et al., “Trends in the postmortem diagnosis of opportunistic invasive fungal infections in patients with AIDS: a retrospective study of 1,630 autopsies performed between 1984 and 2002,” American Journal of Clinical Pathology, vol. 132, no. 2, pp. 221–227, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. G. Schwesinger, D. Junghans, G. Schröder, H. Bernhardt, and M. Knoke, “Candidosis and aspergillosis as autopsy findings from 1994 to 2003,” Mycoses, vol. 48, no. 3, pp. 176–180, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. F. C. Odds, A. D. Davidson, M. D. Jacobsen et al., “Candida albicans strain maintenance, replacement, and microvariation demonstrated by multilocus sequence typing,” Journal of Clinical Microbiology, vol. 44, no. 10, pp. 3647–3658, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. E. Budtz-Jorgensen, “Denture stomatitis. IV. An experimental model in monkeys,” Acta Odontologica Scandinavica, vol. 29, no. 5, pp. 513–526, 1971. View at Google Scholar · View at Scopus
  58. C. Steele, M. Ratterree, and P. L. Fidel, “Differential susceptibility of two species of macaques to experimental vaginal candidiasis,” Journal of Infectious Diseases, vol. 180, no. 3, pp. 802–810, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. K. A. Andrutis, P. J. Riggle, C. A. Kumamoto, and S. Tzipori, “Intestinal lesions associated with disseminated candidiasis in an experimental animal model,” Journal of Clinical Microbiology, vol. 38, no. 6, pp. 2317–2323, 2000. View at Google Scholar · View at Scopus
  60. S. G. Filler, M. A. Crislip, C. L. Mayer, and J. E. Edwards, “Comparison of fluconazole and amphotericin B for treatment of disseminated candidiasis and endophthalmitis in rabbits,” Antimicrobial Agents and Chemotherapy, vol. 35, no. 2, pp. 288–292, 1991. View at Google Scholar · View at Scopus
  61. C. A. Lyman, C. Gonzalez, M. Schneider, J. Lee, and T. J. Walsh, “Effects of the hematoregulatory peptide SKandF 107647 alone and in combination with amphotericin B against disseminated candidiasis in persistently neutropenic rabbits,” Antimicrobial Agents and Chemotherapy, vol. 43, no. 9, pp. 2165–2169, 1999. View at Google Scholar · View at Scopus
  62. A. Polanco, E. Mellado, C. Castilla, and J. L. Rodriguez-Tudela, “Detection of Candida albicans in blood by PCR in a rabbit animal model of disseminated candidiasis,” Diagnostic Microbiology and Infectious Disease, vol. 34, no. 3, pp. 177–183, 1999. View at Publisher · View at Google Scholar
  63. J. Fransen, J. van Cutsem, R. Vandesteene, and P. A. J. Janssen, “Histopathology of experimental systemic candidosis in guinea-pigs,” Sabouraudia, vol. 22, no. 6, pp. 455–469, 1984. View at Google Scholar · View at Scopus
  64. J. van Cutsem and D. Thienpont, “Experimental cutaneous Candida albicans infection in guinea-pigs,” Sabouraudia, vol. 9, no. 1, pp. 17–20, 1971. View at Google Scholar · View at Scopus
  65. J. E. Nett, K. Marchillo, C. A. Spiegel, and D. R. Andes, “Development and validation of an in vivo Candida albicans biofilm denture model,” Infection and Immunity, vol. 78, no. 9, pp. 3650–3659, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. Y. Kamai, M. Kubota, Y. Kamai, T. Hosokawa, T. Fukuoka, and S. G. Filler, “New model of oropharyngeal candidiasis in mice,” Antimicrobial Agents and Chemotherapy, vol. 45, no. 11, pp. 3195–3197, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. Y. H. Samaranayake and L. P. Samaranayake, “Experimental oral candidiasis in animal models,” Clinical Microbiology Reviews, vol. 14, no. 2, pp. 398–429, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. P. L. Fidel Jr. and J. D. Sobel, “Murine models of Candida vaginal infections,” in Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy, O. Zak and M. A. Sande, Eds., pp. 741–748, Academic Press, New York, NY, USA, 1999. View at Google Scholar
  69. C. S. Farah, S. Elahi, K. Drysdale et al., “Primary role for CD4+ T lymphocytes in recovery from oropharyngeal candidiasis,” Infection and Immunity, vol. 70, no. 2, pp. 724–731, 2002. View at Publisher · View at Google Scholar · View at Scopus
  70. J. R. Naglik, P. L. Fidel, and F. C. Odds, “Animal models of mucosal Candida infection,” FEMS Microbiology Letters, vol. 283, no. 2, pp. 129–139, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. F. de Bernardis, R. Lorenzini, and A. Cassone, “Rat model of Candida vaginal infection,” in Handbook of Animal Models of Infection: Experimental Models in Antimicrobial Chemotherapy, O. Zak and M. A. Sande, Eds., pp. 735–740, Academic Press, New York, NY, USA, 1999. View at Google Scholar
  72. D. Rahman, M. Mistry, S. Thavaraj, S. J. Challacombe, and J. R. Naglik, “Murine model of concurrent oral and vaginal Candida albicans colonization to study epithelial host-pathogen interactions,” Microbes and Infection, vol. 9, no. 5, pp. 615–622, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. H. Badrane, M. H. Nguyen, S. Cheng et al., “The Candida albicans phosphatase Inp51 p interacts with the EH domain protein Irs4p, regulates phosphatidylinositol-4,5-bisphosphate levels and influences hyphal formation, the cell integrity pathway and virulence,” Microbiology, vol. 154, no. 11, pp. 3296–3308, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  74. W. P. Holbrook, J. A. Sofaer, and J. C. Southam, “Experimental oral infection of mice with a pathogenic and a non-pathogenic strain of the yeast Candida albicans,” Archives of Oral Biology, vol. 28, no. 12, pp. 1089–1091, 1983. View at Google Scholar · View at Scopus
  75. C. J. Nobile, N. Solis, C. L. Myers et al., “Candida albicans transcription factor Rim101 mediates pathogenic interactions through cell wall functions,” Cellular Microbiology, vol. 10, no. 11, pp. 2180–2196, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. H. Park, C. L. Myers, D. C. Sheppard et al., “Role of the fungal ras-protein kinase a pathway in governing epithelial cell interactions during oropharyngeal candidiasis,” Cellular Microbiology, vol. 7, no. 4, pp. 499–510, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  77. L. Y. Chiang, D. C. Sheppard, V. M. Bruno, A. P. Mitchell, J. E. Edwards, and S. G. Filler, “Candida albicans protein kinase CK2 governs virulence during oropharyngeal candidiasis,” Cellular Microbiology, vol. 9, no. 1, pp. 233–245, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. Z. Chen and X. Kong, “Study of Candida albicans vaginitis model in Kunming mice,” Journal of Huazhong University of Science and Technology, Medical Science, vol. 27, no. 3, pp. 307–310, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  79. K. V. Clemons, J. L. Spearow, R. Parmar, M. Espiritu, and D. A. Stevens, “Genetic susceptibility of mice to Candida albicans vaginitis correlates with host estrogen sensitivity,” Infection and Immunity, vol. 72, no. 8, pp. 4878–4880, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. F. de Bernardis, R. Lorenzini, L. Morelli, and A. Cassone, “Experimental rat vaginal infection with Candida parapsilosis,” FEMS Microbiology Letters, vol. 53, no. 1-2, pp. 137–141, 1989. View at Google Scholar · View at Scopus
  81. J. D. Sobel, G. Muller, and J. F. McCormick, “Experimental chronic vaginal candidosis in rats,” Sabouraudia, vol. 23, no. 3, pp. 199–206, 1985. View at Google Scholar · View at Scopus
  82. M. A. Carrara, L. Donatti, E. Damke, T. I. E. Svidizinski, M. E. L. Consolaro, and M. R. Batista, “A new model of vaginal infection by Candida albicans in rats,” Mycopathologia, vol. 170, no. 5, pp. 331–338, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  83. M. Foldvari, J. Radhi, G. Yang, Z. He, R. Rennie, and L. Wearley, “Acute vaginal candidosis model in the immunocompromized rat to evaluate delivery systems for antimycotics,” Mycoses, vol. 43, no. 11-12, pp. 393–401, 2000. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Tavanti, D. Campa, S. Arancia, L. A. M. Hensgens, F. de Bernardis, and S. Senesi, “Outcome of experimental rat vaginitis by Candida albicans isolates with different karyotypes,” Microbial Pathogenesis, vol. 49, no. 1-2, pp. 47–50, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  85. B. N. Taylor, C. Fichtenbaum, M. Saavedra et al., “In vivo virulence of Candida albicans isolates causing mucosal infections in people infected with the human immunodeficiency virus,” Journal of Infectious Diseases, vol. 182, no. 3, pp. 955–959, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. T. Bader, K. Schröppel, S. Bentink, N. Agabian, G. Köhler, and J. Morschhäuser, “Role of calcineurin in stress resistance, morphogenesis, and virulence of a Candida albicans wild-type strain,” Infection and Immunity, vol. 74, no. 7, pp. 4366–4369, 2006. View at Publisher · View at Google Scholar · View at PubMed
  87. Y. Fu, G. Luo, B. J. Spellberg, J. E. Edwards, and A. S. Ibrahim, “Gene overexpression/suppression analysis of candidate virulence factors of Candida albicans,” Eukaryotic Cell, vol. 7, no. 3, pp. 483–492, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. S. Ferrari, M. Sanguinetti, F. De Bernardis et al., “Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice,” Antimicrobial Agents and Chemotherapy, vol. 55, no. 5, pp. 1852–1860, 2011. View at Publisher · View at Google Scholar · View at PubMed
  89. E. K. Szabo and D. M. MacCallum, “The contribution of mouse models to our understanding of systemic candidiasis,” FEMS Microbiology Letters, vol. 320, no. 1, pp. 1–8, 2011. View at Publisher · View at Google Scholar · View at PubMed
  90. D. B. Louria, R. G. Brayton, and G. Finkel, “Studies on the pathogenesis of experimental Candida albicans infections in mice,” Sabouraudia, vol. 2, pp. 271–283, 1963. View at Google Scholar
  91. J. M. Papadimitriou and R. B. Ashman, “The pathogenesis of acute systemic candidiasis in a susceptible inbred mouse strain,” Journal of Pathology, vol. 150, no. 4, pp. 257–265, 1986. View at Google Scholar · View at Scopus
  92. D. M. MacCallum and F. C. Odds, “Temporal events in the intravenous challenge model for experimental Candida albicans infections in female mice,” Mycoses, vol. 48, no. 3, pp. 151–161, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  93. R. B. Ashman, A. Fulurija, and J. M. Papadimitriou, “Strain-dependent differences in host response to Candida albicans infection in mice are related to organ susceptibility infectious load,” Infection and Immunity, vol. 64, no. 5, pp. 1866–1869, 1996. View at Google Scholar · View at Scopus
  94. B. Spellberg, A. S. Ibrahim, J. E. Edwards, and S. G. Filler, “Mice with disseminated candidiasis die of progressive sepsis,” Journal of Infectious Diseases, vol. 192, no. 2, pp. 336–343, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. D. M. MacCallum, L. Castillo, A. J. P. Brown, N. A. R. Gow, and F. C. Odds, “Early-expressed chemokines predict kidney immunopathology in experimental disseminated Candida albicans infections,” PLoS ONE, vol. 4, no. 7, Article ID e6420, 2009. View at Publisher · View at Google Scholar · View at PubMed
  96. J. R. Graybill, L. K. Najvar, J. D. Holmberg, and M. F. Luther, “Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice,” Antimicrobial Agents and Chemotherapy, vol. 39, no. 4, pp. 924–929, 1995. View at Google Scholar · View at Scopus
  97. L. De Repentigny, M. Phaneuf, and L. G. Mathieu, “Gastrointestinal colonization and systemic dissemination by Candida albicans and Candida tropicalis in intact and immunocompromised mice,” Infection and Immunity, vol. 60, no. 11, pp. 4907–4914, 1992. View at Google Scholar · View at Scopus
  98. F. Bistoni, A. Vecchiarelli, and E. Cenci, “A comparison of experimental pathogenicity of Candida species in cyclophosphamide-immunodepressed mice,” Sabouraudia, vol. 22, no. 5, pp. 409–418, 1984. View at Google Scholar
  99. D. B. Louria, M. Busé, R. G. Brayton, and G. Finkel, “The pathogenesis of Candida tropicalis infections in mice,” Sabouraudia, vol. 5, no. 1, pp. 14–25, 1967. View at Google Scholar · View at Scopus
  100. I. D. Jacobsen, S. Brunke, K. Seider et al., “Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy,” Infection and Immunity, vol. 78, no. 3, pp. 1066–1077, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  101. S. Ferrari, M. Sanguinetti, R. Torelli, B. Posteraro, and D. Sanglard, “Contribution of CgPDR1-regulated genes in enhanced virulence of azole-resistant Candida glabrata,” PLoS ONE, vol. 6, no. 3, 2011. View at Publisher · View at Google Scholar
  102. H. Nakayama, K. Ueno, J. Uno et al., “Growth defects resulting from inhibiting ERG20 and RAM2 in Candida glabrata,” FEMS Microbiology Letters, vol. 317, no. 1, pp. 27–33, 2011. View at Publisher · View at Google Scholar · View at PubMed
  103. A. M. Calcagno, E. Bignell, T. R. Rogers, M. D. Jones, F. A. Mühlschlegel, and K. Haynes, “Candida glabrata Ste11 is involved in adaptation to hypertonic stress, maintenance of wild-type levels of filamentation and plays a role in virulence,” Medical Mycology, vol. 43, no. 4, pp. 355–364, 2005. View at Publisher · View at Google Scholar
  104. A. M. Calcagno, E. Bignell, T. R. Rogers, M. Canedo, F. A. Mühlschleger, and K. Haynes, “Candida glabrata Ste20 is involved in maintaining cell wall integrity and adaptation to hypertonic stress, and is required for wild-type levels of virulence,” Yeast, vol. 21, no. 7, pp. 557–568, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  105. M. Kamran, A. M. Calcagno, H. Findon et al., “Inactivation of transcription factor gene ACE2 in the fungal pathogen Candida glabrata results in hypervirulence,” Eukaryotic Cell, vol. 3, no. 2, pp. 546–552, 2004. View at Publisher · View at Google Scholar · View at Scopus
  106. A. M. Calcagno, E. Bignell, P. Warn et al., “Candida glabrata STE12 is required for wild-type levels of virulence and nitrogen starvation induced filamentation,” Molecular Microbiology, vol. 50, no. 4, pp. 1309–1318, 2003. View at Publisher · View at Google Scholar
  107. E. Mellado, M. Cuenca-Estrella, J. Regadera, M. González, T. M. Díaz-Guerra, and J. L. Rodríguez-Tudela, “Sustained gastrointestinal colonization and systemic dissemination by Candida albicans, Candida tropicalis and Candida parapsilosis in adult mice,” Diagnostic Microbiology and Infectious Disease, vol. 38, no. 1, pp. 21–28, 2000. View at Publisher · View at Google Scholar
  108. F. De Bernardis, L. Morelli, T. Ceddia, R. Lorenzini, and A. Cassone, “Experimental pathogenicity and acid proteinase secretion of vaginal isolates of Candida parapsilosis,” Journal of Medical and Veterinary Mycology, vol. 28, no. 2, pp. 125–137, 1990. View at Google Scholar · View at Scopus
  109. C. Girmenia, P. Martine, F. De Bernardis et al., “Rising incidence of Candida parapsilosis fungemia in patients with hematologic malignancies: clinical aspects, predisposing factors, and differential pathogenicity of the causative strains,” Clinical Infectious Diseases, vol. 23, no. 3, pp. 506–514, 1996. View at Google Scholar
  110. E. Anaissie, R. Hachem, U. C. K-Tin, L. C. Stephens, and G. P. Bodey, “Experimental hematogenous candidiasis caused by candida krusei and Candida albicans: species differences in pathogenicity,” Infection and Immunity, vol. 61, no. 4, pp. 1268–1271, 1993. View at Google Scholar · View at Scopus
  111. C. Y. Koga-Ito, E. Y. Komiyama, C. A. de Paiva Martins et al., “Experimental systemic virulence of oral Candida dubliniensis isolates in comparison with Candida albicans, Candida tropicalis and Candida krusei,” Mycoses, vol. 54, no. 5, pp. e278–e285, 2010. View at Publisher · View at Google Scholar · View at PubMed
  112. H.F. Hasenclever and W. O. Mitchell, “Pathogenicity of C. albicans and C. tropicalis,” Sabouraudia, vol. 1, pp. 16–21, 1961. View at Google Scholar
  113. J. Brieland, D. Essig, C. Jackson et al., “Comparison of pathogenesis and host immune responses to Candida glabrata and Candida albicans in systemically infected immunocompetent mice,” Infection and Immunity, vol. 69, no. 8, pp. 5046–5055, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  114. M. Arendrup, T. Horn, and N. Frimodt-Møller, “In vivo pathogenicity of eight medically relevant Candida species in an animal model,” Infection, vol. 30, no. 5, pp. 286–291, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  115. R. A. Fromtling, G. K. Abruzzo, and D. M. Giltinan, “Candida tropicalis infection in normal, diabetic and neutropenic mice,” Journal of Clinical Microbiology, vol. 25, no. 8, pp. 1416–1420, 1987. View at Google Scholar · View at Scopus
  116. D. M. MacCallum, L. Castillo, K. Nather et al., “Property differences among the four major Candida albicans strain clades,” Eukaryotic Cell, vol. 8, no. 3, pp. 373–387, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  117. P. Sampaio, M. Santos, A. Correia et al., “Virulence attenuation of Candida albicans genetic variants isolated from a patient with a recurrent bloodstream infection,” PLoS ONE, vol. 5, no. 4, Article ID e10155, 2010. View at Publisher · View at Google Scholar · View at PubMed
  118. Y. Okawa, M. Miyauchi, and H. Kobayashi, “Comparison of pathogenicity of various Candida tropicalis strains,” Biological and Pharmaceutical Bulletin, vol. 31, no. 8, pp. 1507–1510, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. A. Cassone, F. De Bernardis, E. Pontieri et al., “Biotype diversity of Candida parapsilosis and its relationship to the clinical source and experimental pathogenicity,” Journal of Infectious Diseases, vol. 171, no. 4, pp. 967–975, 1995. View at Google Scholar · View at Scopus
  120. G. Togni, D. Sanglard, and M. Monod, “Acid proteinase secreted by Candida tropicalis: virulence in mice of a proteinase negative mutant,” Journal of Medical and Veterinary Mycology, vol. 32, no. 4, pp. 257–265, 1994. View at Google Scholar · View at Scopus
  121. S. Ferrari, F. Ischer, D. Calabrese et al., “Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence,” PLoS Pathogens, vol. 5, no. 1, Article ID e1000268, 2009. View at Publisher · View at Google Scholar · View at PubMed
  122. D. M. MacCallum, H. Findon, C. C. Kenny, G. Butler, K. Haynes, and F. C. Odds, “Different consequences of ACE2 and SWI5 gene disruptions for virulence of pathogenic and nonpathogenic yeasts,” Infection and Immunity, vol. 74, no. 9, pp. 5244–5248, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  123. T. Miyazaki, T. Inamine, S. Yamauchi et al., “Role of the Slt2 mitogen-activated protein kinase pathway in cell wall integrity and virulence in Candida glabrata,” FEMS Yeast Research, vol. 10, no. 3, pp. 343–352, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  124. T. Miyazaki, S. Yamauchi, T. Inamine et al., “Roles of calcineurin and Crz1 in antifungal susceptibility and virulence of Candida glabrata,” Antimicrobial Agents and Chemotherapy, vol. 54, no. 4, pp. 1639–1643, 2010. View at Publisher · View at Google Scholar · View at PubMed
  125. T. Saijo, T. Miyazaki, K. Izumikawa et al., “Skn7p is involved in oxidative stress response and virulence of Candida glabrata,” Mycopathologia, vol. 169, no. 2, pp. 81–90, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. G. T. Cole, A. A. Halawa, and E. J. Anaissie, “The role of the gastrointestinal tract in hematogenous candidiasis: from the laboratory to the bedside,” Clinical Infectious Diseases, vol. 22, supplement 2, pp. S73–S88, 1996. View at Google Scholar
  127. S. M. Wiesner, R. P. Jechorek, R. M. Garni, C. M. Bendel, and C. L. Wells, “Gastrointestinal colonization by Candida albicans mutant strains in antibiotic-treated mice,” Clinical and Diagnostic Laboratory Immunology, vol. 8, no. 1, pp. 192–195, 2001. View at Publisher · View at Google Scholar · View at PubMed
  128. K. V. Clemons, G. M. Gonzalez, G. Singh et al., “Development of an orogastrointestinal mucosal model of candidiasis with dissemination to visceral organs,” Antimicrobial Agents and Chemotherapy, vol. 50, no. 8, pp. 2650–2657, 2006. View at Publisher · View at Google Scholar · View at PubMed
  129. H. Sandovsky-Losica, L. Barr-Nea, and E. Segal, “Fatal systemic candidiasis of gastrointestinal origin: an experimental model in mice compromised by anti-cancer treatment,” Journal of Medical and Veterinary Mycology, vol. 30, no. 3, pp. 219–231, 1992. View at Google Scholar · View at Scopus
  130. A. Y. Koh, J. R. Köhler, K. T. Coggshall, N. Van Rooijen, and G. B. Pier, “Mucosal damage and neutropenia are required for Candida albicans dissemination,” PLoS Pathogens, vol. 4, no. 2, p. e35, 2008. View at Publisher · View at Google Scholar · View at PubMed
  131. M. T. Cantorna and E. Balish, “Mucosal and systemic candidiasis in congenitally immunodeficient mice,” Infection and Immunity, vol. 58, no. 4, pp. 1093–1100, 1990. View at Google Scholar · View at Scopus
  132. M. J. Kennedy and P. A. Volz, “Dissemination of yeasts after gastrointestinal inoculation in antibiotic-treated mice,” Sabouraudia, vol. 21, no. 1, pp. 27–33, 1983. View at Google Scholar · View at Scopus
  133. J. R. Wingard, J. D. Dick, and W. G. Merz, “Pathogenicity of Candida tropicalis and Candida albicans after gastrointestinal inoculation in mice,” Infection and Immunity, vol. 29, no. 2, pp. 808–813, 1980. View at Google Scholar
  134. J. R. Wingard, J. D. Dick, and W. G. Merz, “Differences in virulence of clinical isolates of Candida tropicalis and Candida albicans in mice,” Infection and Immunity, vol. 37, no. 2, pp. 833–836, 1982. View at Google Scholar
  135. M. S. Skrzypek, M. B. Arnaud, M. C. Costanzo et al., “New tools at the Candida genome database: biochemical pathways and full-text literature search,” Nucleic Acids Research, vol. 38, pp. D428–D432, 2010. View at Publisher · View at Google Scholar · View at PubMed
  136. C. M. Bendel, D. J. Hess, R. M. Garni, M. Henry-Stanley, and C. L. Wells, “Comparative virulence of Candida albicans yeast and filamentous forms in orally and intravenously inoculated mice,” Critical Care Medicine, vol. 31, no. 2, pp. 501–507, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  137. C. Westwater, D. A. Schofield, P. J. Nicholas, E. E. Paulling, and E. Balish, “Candida glabrata and Candida albicans; dissimilar tissue tropism and infectivity in a gnotobiotic model of mucosal candidiasis,” FEMS Immunology and Medical Microbiology, vol. 51, no. 1, pp. 134–139, 2007. View at Publisher · View at Google Scholar · View at PubMed
  138. G. Butler, M. D. Rasmussen, M. F. Lin et al., “Evolution of pathogenicity and sexual reproduction in eight Candida genomes,” Nature, vol. 459, no. 7247, pp. 657–662, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  139. B. Dujon, D. Sherman, G. Fischer et al., “Genome evolution in yeasts,” Nature, vol. 430, no. 6995, pp. 35–44, 2004. View at Publisher · View at Google Scholar · View at PubMed
  140. S. M. Noble, S. French, L. A. Kohn, V. Chen, and A. D. Johnson, “Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity,” Nature Genetics, vol. 42, no. 7, pp. 590–598, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  141. J. M. Becker, S. J. Kauffman, M. Hauser et al., “Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 51, pp. 22044–22049, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  142. K. Kavanagh and E. P. Reeves, “Exploiting the potential of insects for in vivo pathogenicity testing of microbial pathogens,” FEMS Microbiology Reviews, vol. 28, no. 1, pp. 101–112, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  143. G. Cotter, S. Doyle, and K. Kavanagh, “Development of an insect model for the in vivo pathogenicity testing of yeasts,” FEMS Immunology and Medical Microbiology, vol. 27, no. 2, pp. 163–169, 2000. View at Publisher · View at Google Scholar
  144. M. Brennan, D. Y. Thomas, M. Whiteway, and K. Kavanagh, “Correlation between virulence of Candida albicans mutants in mice and Galleria mellonella larvae,” FEMS Immunology and Medical Microbiology, vol. 34, no. 2, pp. 153–157, 2002. View at Publisher · View at Google Scholar
  145. B. B. Fuchs, J. Eby, C. J. Nobile, J. B. El Khoury, A. P. Mitchell, and E. Mylonakis, “Role of filamentation in Galleria mellonella killing by Candida albicans,” Microbes and Infection, vol. 12, no. 6, pp. 488–496, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. G. B. Dunphy, U. Oberholzer, M. Whiteway, R. J. Zakarian, and I. Boomer, “Virulence of Candida albicans mutants toward larval Galleria mellonella (Insecta, Lepidoptera, Galleridae),” Canadian Journal of Microbiology, vol. 49, no. 8, pp. 514–524, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. N. Hanaoka, Y. Takano, K. Shibuya, H. Fugo, Y. Uehara, and M. Niimi, “Identification of the putative protein phosphatase gene PTC1 as a virulence-related gene using a silkworm model of Candida albicans infection,” Eukaryotic Cell, vol. 7, no. 10, pp. 1640–1648, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  148. H. Hamamoto, K. Kurokawa, C. Kaito et al., “Quantitative evaluation of the therapeutic effects of antibiotics using silkworms infected with human pathogenic microorganisms,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 3, pp. 774–779, 2004. View at Publisher · View at Google Scholar
  149. G. Chamilos, M. S. Lionakis, R. E. Lewis et al., “Drosophila melanogaster as a facile model for large-scale studies of virulence mechanisms and antifungal drug efficacy in Candida species,” Journal of Infectious Diseases, vol. 193, no. 7, pp. 1014–1022, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  150. A. M. Alarco, A. Marcil, J. Chen, B. Suter, D. Thomas, and M. Whiteway, “Immune-Deficient Drosophila melanogaster: a model for the innate immune response to human fungal pathogens,” Journal of Immunology, vol. 172, no. 9, pp. 5622–5628, 2004. View at Google Scholar · View at Scopus
  151. M. T. Glittenberg, S. Silas, D. M. MacCallum, N. A.R. Gow, and P. Ligoxygakis, “Wild-type Drosophila melanogaster as an alternative model system for investigating the pathogenicity of Candida albicans,” DMM Disease Models and Mechanisms, vol. 4, no. 4, pp. 504–514, 2011. View at Publisher · View at Google Scholar · View at PubMed
  152. M. T. Glittenberg, I. Kounatidis, D. Christensen et al., “Pathogen and host factors are needed to provoke a systemic host response to gastrointestinal infection of Drosophila larvae by Candida albicans,” DMM Disease Models and Mechanisms, vol. 4, no. 4, pp. 515–525, 2011. View at Publisher · View at Google Scholar · View at PubMed
  153. R. A. Hall, L. de Sordi, D. M. MacCallum et al., “CO2 acts as a signalling molecule in populations of the fungal pathogen Candida albicans,” PLoS Pathogens, vol. 6, no. 11, 2010. View at Publisher · View at Google Scholar
  154. G. Chamilos, C. J. Nobile, V. M. Bruno, R. E. Lewis, A. P. Mitchell, and D. P. Kontoyiannis, “Candida albicans Cas5, a regulator of cell wall integrity, is required for virulence in murine and toll mutant fly models,” Journal of Infectious Diseases, vol. 200, no. 1, pp. 152–157, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. R. Pukkila-Worley, A. Y. Peleg, E. Tampakakis, and E. Mylonakis, “Candida albicans hyphal formation and virulence assessed using a Caenorhabditis elegans infection model,” Eukaryotic Cell, vol. 8, no. 11, pp. 1750–1758, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  156. N. D. Meeker and N. S. Trede, “Immunology and zebrafish: spawning new models of human disease,” Developmental and Comparative Immunology, vol. 32, no. 7, pp. 745–757, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  157. J. P. Levraud, E. Colucci-Guyon, M. J. Redd, G. Lutfalla, and P. Herbomel, “In vivo analysis of zebrafish innate immunity,” Methods in Molecular Biology, vol. 415, pp. 337–363, 2008. View at Google Scholar · View at Scopus
  158. C. C. Chao, P. C. Hsu, C. F. Jen et al., “Zebrafish as a model host for Candida albicans infection,” Infection and Immunity, vol. 78, no. 6, pp. 2512–2521, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. H. J. Lo, J. R. Köhler, B. Didomenico, D. Loebenberg, A. Cacciapuoti, and G. R. Fink, “Nonfilamentous C. albicans mutants are avirulent,” Cell, vol. 90, no. 5, pp. 939–949, 1997. View at Publisher · View at Google Scholar · View at Scopus
  160. G. G. Chen, Y. L. Yang, H. H. Cheng et al., “Non-lethal Candida albicans cph1/cph1 efg1/efg1 transcription factor mutant establishing restricted zone of infection in a mouse model of systemic infection,” International Journal of Immunopathology and Pharmacology, vol. 19, no. 3, pp. 561–565, 2006. View at Google Scholar
  161. R. M. White, A. Sessa, C. Burke et al., “Transparent adult zebrafish as a tool for in vivo transplantation analysis,” Cell Stem Cell, vol. 2, no. 2, pp. 183–189, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  162. K. M. Brothers, Z. R. Newman, and R. T. Wheeler, “Live imaging of disseminated candidiasis in zebrafish reveals role of phagocyte oxidase in limiting filamentous growth,” Eukaryotic Cell, vol. 10, no. 7, pp. 932–944, 2011. View at Publisher · View at Google Scholar · View at PubMed
  163. D. C. Savage and R. J. Dubos, “Localization of indigenous yeast in the murine stomach,” The Journal of Bacteriology, vol. 94, no. 6, pp. 1811–1816, 1967. View at Google Scholar
  164. N. V. Sipsas, R. E. Lewis, J. Tarrand et al., “Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001–2007): stable incidence but changing epidemiology of a still frequently lethal infection,” Cancer, vol. 115, no. 20, pp. 4745–4752, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  165. M. Rehli, “Of mice and men: species variations of Toll-like receptor expression,” Trends in Immunology, vol. 23, no. 8, pp. 375–378, 2002. View at Publisher · View at Google Scholar · View at Scopus
  166. X. Jiang, C. Shen, H. Yu, K. P. Karunakaran, and R. C. Brunham, “Differences in innate immune responses correlate with differences in murine susceptibility to Chlamydia muridarum pulmonary infection,” Immunology, vol. 129, no. 4, pp. 556–566, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  167. D. L. Gibbons and J. Spencer, “Mouse and human intestinal immunity: same ballpark, different players; different rules, same score,” Mucosal Immunology, vol. 4, no. 2, pp. 148–157, 2011. View at Publisher · View at Google Scholar · View at PubMed
  168. J. Mestas and C. C. W. Hughes, “Of mice and not men: differences between mouse and human immunology,” Journal of Immunology, vol. 172, no. 5, pp. 2731–2738, 2004. View at Google Scholar · View at Scopus
  169. G. Marquis, S. Montplaisir, M. Pelletier, P. Auger, and W. S. Lapp, “Genetics of resistance to infection with Candida albicans in mice,” British Journal of Experimental Pathology, vol. 69, no. 5, pp. 651–660, 1988. View at Google Scholar · View at Scopus
  170. G. Marquis, S. Montplaisir, and M. Pelletier, “Strain-dependent differences in susceptibility of mice to experimental candidosis,” Journal of Infectious Diseases, vol. 154, no. 5, pp. 906–909, 1986. View at Google Scholar
  171. R. B. Ashman, E. M. Bolitho, and J. M. Papadimitriou, “Patterns of resistance to Candida albicans in inbred mouse strains,” Immunology and Cell Biology, vol. 71, no. 3, pp. 221–225, 1993. View at Google Scholar · View at Scopus
  172. I. Radovanovic, A. Mullick, and P. Gros, “Genetic control of susceptibility to infection with Candida albicans in mice,” PLoS ONE, vol. 6, no. 4, 2011. View at Publisher · View at Google Scholar
  173. F. De Bernardis, D. Adriani, R. Lorenzini, E. Pontieri, G. Carruba, and A. Cassone, “Filamentous growth and elevated vaginopathic potential of a nongerminative variant of Candida albicans expressing low virulence in systemic infection,” Infection and Immunity, vol. 61, no. 4, pp. 1500–1508, 1993. View at Google Scholar · View at Scopus
  174. E. Balish, “A URA3 null mutant of Candida albicans (CAI-4) causes oro-oesophageal and gastric candidiasis and is lethal for gnotobiotic, transgenic mice (Tgε26) that are deficient in both natural killer and T cells,” Journal of Medical Microbiology, vol. 58, no. 3, pp. 290–295, 2009. View at Publisher · View at Google Scholar · View at PubMed
  175. A. Brand, D. M. MacCallum, A. J. P. Brown, N. A. R. Gow, and F. C. Odds, “Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus,” Eukaryotic Cell, vol. 3, no. 4, pp. 900–909, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  176. J. Lay, L. K. Henry, J. Clifford, Y. Koltin, C. E. Bulawa, and J. M. Becker, “Altered expression of selectable marker URA3 in gene-disrupted Candida albicans strains complicates interpretation of virulence studies,” Infection and Immunity, vol. 66, no. 11, pp. 5301–5306, 1998. View at Google Scholar · View at Scopus
  177. P. Sundstrom, J. E. Cutler, and J. F. Staab, “Reevaluation of the role of HWP1 in systemic candidiasis by use of Candida albicans strains with selectable marker URA3 targeted to the ENO1 locus,” Infection and Immunity, vol. 70, no. 6, pp. 3281–3283, 2002. View at Publisher · View at Google Scholar · View at Scopus