Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis
Open accessAbstract
BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.
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A genomic analysis of clinical C. neoformans isolates found a high rate of aneuploidy in heteroresistant colonies and recurrent isolates, with a predominance of chr1 disomy.
“A genomic analysis of clinical C. neoformans isolates found a high rate of aneuploidy in heteroresistant colonies and recurrent isolates, with a predominance of chr1 disomy [142].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [142]
A genomic analysis of clinical C. neoformans strains found a high rate of aneuploidy in heteroresistant colonies and recurrent isolates, with a predominance of chr1 disomy and up-regulated activity of efflux pumps.
“A genomic analysis of clinical C. neoformans strains found a high rate of aneuploidy in heteroresistant colonies and recurrent isolates, with a predominance of chr1 disomy and up-regulated activity of efflux pumps [142].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [142]
A study of C. neoformans showed that 5-FC effectively suppresses fluconazole-induced heteroresistance.
“A study of C. neoformans showed that 5-FC effectively suppress fluconazole-induced heteroresistance, suggesting the importance of combined therapy [142].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [142]
5-FC suppression of fluconazole-induced heteroresistance suggests importance of combined therapy.
“A study of C. neoformans showed that 5-FC effectively suppress fluconazole-induced heteroresistance, suggesting the importance of combined therapy [142].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [142]
Heteroresistance primarily occurs through the formation of aneuploid cells, both in vitro and in vivo.
“Heteroresistance primarily occurs through the formation of aneuploid cells, both in vitro and in vivo17,22,24 (Fig. 1)”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [22]
Heteroresistance has major clinical implications, as the proportion of resistant cells increases over the course of therapy, making this mechanism a major contributor to relapse during azole maintenance therapy.
“Heteroresistance has major clinical implications, as the proportion of resistant cells increases over the course of therapy, making this mechanism a major contributor to relapse during azole maintenance therapy22,23.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [22]
Aneuploidy has been reported for chromosomes 6, 10, 11 and 14, although the specific genetic elements responsible for the selective advantage remain unclear.
“Aneuploidy has been reported for other chromosomes, including chromosomes 6, 10, 11 and 14, although the specific genetic elements responsible for the selective advantage remain unclear17,22,25,26.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [22]
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- Authors
- Stone, N. R. H., Rhodes, J., Fisher, M. C., Mfinanga, S., Kivuyo, S., Rugemalila, J., Segal, E. S., Needleman, L., Molloy, S. F., Kwon-Chung, J., Harrison, T. S., Hope, W., Berman, J., & Bicanic, T.
- Affiliations
- University of London (GB)
- Imperial College London (GB)
- Liverpool School of Tropical Medicine (GB)
- National Institute for Medical Research (TZ)
- Muhimbili National Hospital (TZ)
- Tel Aviv University (IL)
- University of Liverpool (GB)
- Corresponding author
- Stone, Neil R.H.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2019-01-28
- Volume
- 129
- Issue
- 3
- Pages
- 999-1014
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6391087
- OpenAlex
- W2913110287
- Cited by
- 167
- References
- 55
- Citations by year
- 2026: 22 · 2025: 19 · 2024: 27 · 2023: 20 · 2022: 23 · 2021: 24 · 2020: 17 · 2019: 15
- FWCI
- 15.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
- LSTM Online Archive (Liverpool School of Tropical Medicine) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (097377/Z/11/Z.)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- cryptococcal meningitis, fluconazole resistance, heteroresistance, aneuploidy, ploidy changes, Cryptococcus neoformans, Cryptococcus gattii, HIV-associated cryptococcosis, ERG11, relapse, cerebrospinal fluid
- MeSH terms
- Cryptococcus neoformans, Female, Humans, Male, Ploidies, Fluconazole, Meningitis, Cryptococcal, Drug Resistance, Fungal, Cryptococcus gattii
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