Medical Mycology Book Pdf
Edilma Howard
Medical Mycology and Fungal Immunology MRes course, covering all aspects of medical mycology, immunity, the molecular basis of infection, and the genomics of infectious disease.
Of all microbial pathogens of humans, fungi are the least well studied and understood. The cost of diagnosing and treating fungal infections also has major economic impact. The MRC Centre for Medical Mycology (MRC CMM) enables this group of researchers to utilise and expand its critical mass, promoting pioneering cross-disciplinary research that covers areas of scientific, translational and clinical importance.
The MRC CMM, recently relocated to the University of Exeter, is a joint investment by the MRC and the University of Exeter and represents one of the most ambitious strategic investments in medical mycology worldwide. The MRC CMM is based in the Geoffrey Pope building within the Faculty of Health and Life Sciences (HLS).
**Clinical experts in Medical Mycology will be presenting cases highlighting the challenges and new observations in the clinical recognition, diagnosis and management of fungal diseases**
The MRC Centre of Medical Mycology (MRC CMM) welcomes enquiries from excellent researchers who wish to submit a fellowship application to an external funder (for example UKRI, Wellcome Trust, Royal Society) and be hosted by the MRC Centre of Medical Mycology.
We are particularly interested in recruiting researchers focused upon co-infections and antimicrobial resistance, and welcome discussions with non-mycological applicants having research portfolios that can incorporate medically important fungal pathogens.
We recommend that you first contact the Centre, or an individual academic to discuss your ideas. Secondly, please complete our form at the link below and attach your supporting information. We have an internal mentoring process to ensure that the applications we support are of the highest standard
The MRC CMM welcomes applications from postgraduate research (PGR) students, post-doctoral researchers, medical students and clinicians wishing to pursue research questions, gain invaluable experience in cutting edge technologies and experimental design, or to obtain focused training in specific research areas within medical mycology.
A major activity of the Centre is to increase capacity in fundamental and clinical research in medical mycology through research and training programmes for medical and biosciences students, clinicians and early career researchers.
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Of the estimated five million species of fungi, less than 100 species are frequent agents of human disease, and most deaths are due to organisms within the genera Candida, Aspergillus and Cryptococcus3. However, a cadre of new emerging pathogens are rising in clinical importance, and these include some highly drug-resistant species, including Scopulariopsis and Lomentospora11. Antifungal resistance. This can be a consequence of the response to patient antifungal treatment, but many human pathogenic fungi also have an environmental phase where resistance can emerge12. For example, antifungal resistance in Aspergillus fumigatus is clearly associated with environmental selection of resistance as a consequence of exposure to agricultural azoles used in crop protection13. Indeed, estimates suggest that one in 20 culturable isolates of this fungus isolated from the air are tebuconazole resistant14. Some strains of Candida glabrata, Candida krusei, most strains of Scedosporium and the Mucorales, and the recent emergent species Candida auris display reduced susceptibility to commonly used antifungals. The problems of antifungal resistance are compounded by problems of late diagnosis and consequently treatment delays. Very high levels of morbidity and mortality1 are associated with comorbidities, (e.g., haematological malignancies, solid organ transplantation, ICU stays, HIV, SARS-CoV-2, and influenza), rising numbers of susceptible hosts, host immune status, drug accessibility, drug tolerance, treatment with biologics and the formation of fungal biofilms. Life-threatening fungal infections also tend to be prevalent in resource-limited areas of the world with fewer health care options, including access to antifungal diagnostics and drugs. Low- and middle-income countries face additional challenges, including indiscriminate use of antifungal drugs, and limited stewardship15,16. Cumulatively, these factors result in hundreds of millions of serious fungal infections and between 1 and 1.5 million attributed fungal infection-related deaths per year1,2.
This review summarizes the conclusions of a workshop hosted by the Medical Research Council and the University of Exeter in May 2021. The workshop brought together a group of medical mycologists with diverse research interests (Supplementary Table 1) to outline the scale of the threat and the opportunities to mitigate the consequences of antifungal resistance.
Sensu-stricto, antifungal drug resistance, like antibacterial drug resistance, is the ability of a fungal isolate to grow well in the presence of drug concentrations that inhibit the growth of most isolates of that species. To formalize and quantify susceptibility for clinical microbiology labs, two major consortia, the Clinical & Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) have defined breakpoints as the minimal inhibitory concentration (MIC) of a drug, above which an isolate is considered resistant to clinical treatment, as well as epidemiologic cut-off values (ECVs or ECOFFs) that define the upper limit of the wild type susceptible population when breakpoints are unavailable23. Drug-resistant isolates are more likely to fail treatment and to cause breakthrough infections24.
Antifungal drug resistance is usually due to stable and heritable point mutations or insertions/deletions that directly affect the interaction of the drug with its target (Fig. 1)20,25. In addition to antifungal drug resistance, several more subtle drug responses that may have clinical significance have been studied primarily in yeasts. These include tolerance, heteroresistance, biofilm formation, aneuploidy, and persistence (reviewed in ref. 26).
Biofilms are a physiological adaptation to surface attachment that enables survival in the face of antifungal drugs, via multiple mechanisms, including sequestration of the drug in the extracellular matrix material that is secreted in extracellular vesicles28,41. The physiological changes that accompany biofilm formation are transient, being lost when cells exit the biofilm state and grow as yeast. Biofilms are influenced by genetic background29 and can exhibit increased drug resistance and drug tolerance, although the degree of overlap between these processes remains to be explored. Finally, persistence is a concept seen in bacteria treated with bactericidal drugs, where rare (>0.1% of the population for most commonly used antibiotics42), metabolically quiescent cells survive by not metabolizing the cidal drug. Antifungal persistence was associated with biofilms in one study, but it has been more difficult to detect (reviewed in ref. 43) and its relevance remains controversial44.
Genetic background plays a major role in antifungal tolerance, with the degree of tolerance much higher in some clinical isolates than others, such as fluconazole tolerance in Candida albicans35,36. In addition, tolerance is more evident with fungistatic drugs like azoles, yet is seen with fungicidal drugs such as echinocandins in some species. It appears that C. auris (Box 1) is highly resistant to azoles and also exhibits high levels of azole tolerance45,46,47. In C. glabrata, mitochondria play a role in the appearance of tolerance to echinocandins48.
Tolerance or trailing growth is not quantified in diagnostic assays. However, tolerance can be measured via minor modifications of current susceptibility assays35,36,49. Several small-scale studies suggested that higher tolerance of invasive C. albicans strains contribute to treatment failures and increased patient mortality36,50,51. Larger clinical studies are needed to determine the degree to which tolerance plays a role in treatment failures. In addition, understanding how the complex circuitry that allows cells (or only some cells) to grow under stress conditions is an important challenge currently being explored with a range of approaches.
One major approach to studying the acquisition of resistance and tolerance is experimental evolution in the presence of inhibitory or sub-inhibitory drug concentrations. Inhibitory drug concentrations select for the rare resistant isolates, while sub-inhibitory concentrations often enable the appearance of tolerant cells52. The effects of variables such as the genetic background of the starting isolate and/or differences in culture conditions (in vitro and in animal models) can be evaluated by their effect on the rate of resistance mutation appearance. The evolved progeny can be analyzed using selective screens that either sequence only specific genes known to be involved in resistance (e.g., direct targets of azoles (ERG11/CYP51A) or echinocandins (FKS1/FKS2), or that use genome-wide sequencing to identify potential new resistance and tolerance mechanisms by comparing them to the progenitor strain sequence53,54,55). Mutations that affect levels of drug transporters, can also be found in highly resistant isolates55 and mutations in genes that affect stress response pathways are expected in tolerant isolates.
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