A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection
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Abstract
Recurrence of meningitis due to Cryptococcus neoformans after treatment causes substantial mortality in HIV/AIDS patients across sub-Saharan Africa. In order to determine whether recurrence occurred due to relapse of the original infecting isolate or reinfection with a different isolate weeks or months after initial treatment, we used whole-genome sequencing (WGS) to assess the genetic basis of infection in 17 HIV-infected individuals with recurrent cryptococcal meningitis (CM). Comparisons revealed a clonal relationship for 15 pairs of isolates recovered before and after recurrence showing relapse of the original infection. The two remaining pairs showed high levels of genetic heterogeneity; in one pair we found this to be a result of infection by mixed genotypes, while the second was a result of nonsense mutations in the gene encoding the DNA mismatch repair proteins MSH2, MSH5, and RAD5. These nonsense mutations led to a hypermutator state, leading to dramatically elevated rates of synonymous and nonsynonymous substitutions. Hypermutator phenotypes owing to nonsense mutations in these genes have not previously been reported in C. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.
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Patients treated for cryptococcal meningitis often relapse due to gain of resistance to antifungal drugs.
“Patients treated for cryptococcal meningitis often relapse due to gain of resistance to antifungal drugs (35).”
From Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus <i>Cryptococcus neoformans</i> (2017) · cites this paper as [35]
In a study investigating the causes of recurrence of meningitis due to C. neoformans, one isolate with a mutation in the MSH2 gene was identified.
“Recently, in a study investigating the causes of recurrence of meningitis due to C. neoformans, one isolate with a mutation in the MSH2 gene was identified (35).”
From Mismatch Repair of DNA Replication Errors Contributes to Microevolution in the Pathogenic Fungus <i>Cryptococcus neoformans</i> (2017) · cites this paper as [35]
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References 65 · Cited by 100
Research works printed but not linked: 2
- Burns J. L. Gibson R. L. McNamara S. Yim D. Emerson J., 2001 Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J. Infect. Dis. 183(3): 444– 452. 11133376
- Meyer W. Aanensen D. M. Boekhout T. Cogliati M. Diaz M. R., 2009 Consensus multi-locus sequence typing scheme for Cryptococcus neoformans and Cryptococcus gattii. Med. Mycol. 47(6): 561– 570. 19462334 PMC2884100
- Authors
- Rhodes, J., Beale, M. A., Vanhove, M., Jarvis, J. N., Kannambath, S., Simpson, J. A., Ryan, A., Meintjes, G., Harrison, T. S., Fisher, M. C., & Bicanic, T.
- Affiliations
- Imperial College London (GB)
- University College London (GB)
- London School of Hygiene & Tropical Medicine (GB)
- St George's, University of London (GB)
- National Health Laboratory Service (ZA)
- University of Cape Town (ZA)
- Corresponding author
- Fisher, Matthew C
- Bicanic, Tihana
- ORCID
- Venue
- G3 Genes|Genomes|Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-01
- Volume
- 7
- Issue
- 4
- Pages
- 1165-1176
- ISSN
- 2160-1836 (ISSN-L)
- PMC
- PMC5386865
- OpenAlex
- W2586809048
- Cited by
- 100
- References
- 65
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 7 · 2023: 13 · 2022: 14 · 2021: 14 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 9
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- G3 Genes Genomes Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- St George's Online Research Archive (St George's University of London) (submittedVersion)
- HAL (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- University of Pennsylvania (P30 AI 045008)
- Wellcome Trust (/WT081794)
- Imperial College London
- National Institutes of Health
- Center for AIDS Research, University of Washington (P30-AI-045008)
- Medical Research Council (MR/K000373/1, K000373/1)
- National Institute of Allergy and Infectious Diseases (P30AI045008)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic diversity and population structure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- Cryptococcus neoformans, relapse versus reinfection, clonal relatedness, mixed genotypes, DNA mismatch repair, MSH2, MSH5, Rad5, nonsense mutation, hypermutator phenotype, antifungal resistance, HIV/AIDS, synonymous and nonsynonymous substitutions
- MeSH terms
- Adult, Aneuploidy, Cryptococcus neoformans, Demography, Biological Evolution, Female, Genetics, Population, Humans, Male, Microbial Sensitivity Tests, Phylogeny, Recurrence, Genetic Variation, Chromosomes, Fungal, Meningitis, Cryptococcal, Sequence Analysis, DNA, Codon, Nonsense, Polymorphism, Single Nucleotide, Genomics, DNA Mismatch Repair, Host-Pathogen Interactions, DNA Copy Number Variations
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