Levels of glucose present in the brain may contribute to the development of antifungal tolerance in Cryptococcus neoformans — a new study published in Nature Microbiology reports by research group led by Professpr WANG Linqi of the Institute of Microbiology, Chinese Academy of Sciences . These findings, based on data from mice and human cerebrospinal fluid, may have relevance for the treatment of fungal meningitis.Tolerance to fungicides, which are used to treat fungal diseases, allows fungi to survive killing by fungicides, but it is unknown whether host-derived factors can induce fungicide tolerance, affecting therapeutic strategies against fungal diseases C. neoformans, a fungus that infects the human brain, is the leading cause of fungal meningitis and leads to around 180,000 deaths per year. Currently, the only fungicidal drug available to treat it is amphotericin B.
Prof. WANG Linqi and colleagues conduct a high-throughput screen, validated in brain tissue from mice and human cerebrospinal fluid, to explore the effect of hundreds of metabolites on the interactions between C. neoformans and amphotericin B. They identified that glucose present in the brain elicits antifungal tolerance through the C. neoformans protein, Mig1, which is a regulator of glucose repression. In mice, the authors show that Mig1 inhibits the synthesis of ergosterol, a component of fungal cell membranes, which is the target of amphotericin B and promotes the production of inositolphosphorylceramide (another component of fungal cell membranes), which competes with amphotericin B for ergosterol, limiting the drug’s effectiveness. The researchers then demonstrate that using an inhibitor of inositolphosphorylceramide together with amphotericin B improves treatment efficacy against cryptococcal meningitis in mice.
These findings indicate that fungal drug tolerance can be induced by host-derived metabolites and the authors conclude that this could inspire the development of effective therapies targeting fungal diseases.
This work was supported by the National Key Research and Development Program, the National Natural Science Foundation of China and the CAS Interdisciplinary Innovation Team.
Figure: Schematic diagram showing a model of glucose-induced AmB tolerance during cryptococcal meningitis. (Image by Prof. WANG Linqi’s group)
Contact:
WANG Linqi
Institute of Microbiology, Chinese Academy of Sciences
Phone: 86-010-64806184
E-mail: wanglq@im.ac.cn
Research
