title: A Population Genomics Approach to Assessing the Genetic Basis of Within-Host Microevolution Underlying Recurrent Cryptococcal Meningitis Infection.
abstract: Recurrence of meningitis due toCryptococcus neoformansafter 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 proteinsMSH2,MSH5, andRAD5These 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 inC. neoformans, and represent a novel pathway for rapid within-host adaptation and evolution of resistance to first-line antifungal drugs.
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom.
authors.forename: Johanna
authors.identifier: 0000-0002-1338-7860
authors.initials: J
authors.lastname: Rhodes
authors.affiliation: Division of Infection and Immunity, Faculty of Medical Sciences, University College London, WC1E 6BT United Kingdom.
authors.forename: Mathew A
authors.identifier: 0000-0002-4740-3187
authors.initials: MA
authors.lastname: Beale
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vanhove
authors.affiliation: Botswana-UPenn Partnership, 0022 Gaborone, Botswana.|Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.|Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, WC1E 7HT, United Kingdom.
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Jarvis
authors.affiliation: Institute of Infection and Immunity, St. George's University London, SW17 0RE United Kingdom.
authors.forename: Shichina
authors.identifier: 0000-0002-4758-9161
authors.initials: S
authors.lastname: Kannambath
authors.affiliation: National Health Laboratory Service, Greenpoint, Cape Town, 8005 South Africa.
authors.forename: John A
authors.initials: JA
authors.lastname: Simpson
authors.affiliation: National Health Laboratory Service, Greenpoint, Cape Town, 8005 South Africa.
authors.forename: Anthea
authors.initials: A
authors.lastname: Ryan
authors.affiliation: Department of Medicine, University of Cape Town, 7925, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Institute of Infection and Immunity, St. George's University London, SW17 0RE United Kingdom.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Harrison
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, W2 1PG United Kingdom matthew.fisher@imperial.ac.uk tbicanic@sgul.ac.uk.
authors.forename: Matthew C
authors.identifier: 0000-0002-1862-6402
authors.initials: MC
authors.lastname: Fisher
authors.affiliation: Institute of Infection and Immunity, St. George's University London, SW17 0RE United Kingdom matthew.fisher@imperial.ac.uk tbicanic@sgul.ac.uk.
authors.forename: Tihana
authors.initials: T
authors.lastname: Bicanic
mesh_terms: D000328:Adult; D000782:Aneuploidy; D005075:Biological Evolution; D015825:Chromosomes, Fungal / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D003455:Cryptococcus neoformans / Q000302:isolation & purification / Q000502:physiology*; D056915:DNA Copy Number Variations / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D003710:Demography; D005260:Female; D014644:Genetic Variation; D005828:Genetics, Population; D023281:Genomics; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D008297:Male; D016919:Meningitis, Cryptococcal / Q000235:genetics* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012008:Recurrence; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense
keywords: cryptococcosis; evolution; genomics; hypermutation; resistance