Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>

ABSTRACT The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yuan Chen, Rhys A. Farrer, Charles Giamberardino, Sharadha Sakthikumar, Alexander Jones, Timothy Yang, Jennifer L. Tenor, Omar Wagih, Marelize Van Wyk, Nelesh P. Govender, Thomas G. Mitchell, Anastasia P. Litvintseva, Christina A. Cuomo, John R. Perfect
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b5c9bad0bd6a426ba1fe07c9374e5456
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b5c9bad0bd6a426ba1fe07c9374e5456
record_format	dspace
spelling	oai:doaj.org-article:b5c9bad0bd6a426ba1fe07c9374e54562021-11-15T15:50:59ZMicroevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>10.1128/mBio.00166-172150-7511https://doaj.org/article/b5c9bad0bd6a426ba1fe07c9374e54562017-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00166-17https://doaj.org/toc/2150-7511ABSTRACT The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and relapse isolates may reveal evidence of determinative, microevolutionary changes within the host. Here, we analyzed serial isolates cultured from cerebrospinal fluid specimens of 18 South African patients with recurrent cryptococcal meningitis. The time between collection of the incident isolates and collection of the relapse isolates ranged from 124 days to 290 days, and the analyses revealed that, during this period within the patients, the isolates underwent several genetic and phenotypic changes. Considering the vast genetic diversity of cryptococcal isolates in sub-Saharan Africa, it was not surprising to find that the relapse isolates had acquired different genetic and correlative phenotypic changes. They exhibited various mechanisms for enhancing virulence, such as growth at 39°C, adaptation to stress, and capsule production; a remarkable amplification of ERG11 at the native and unlinked locus may provide stable resistance to fluconazole. Our data provide a deeper understanding of the microevolution of Cryptococcus species under pressure from antifungal chemotherapy and host immune responses. This investigation clearly suggests a promising strategy to identify novel targets for improved diagnosis, therapy, and prognosis. IMPORTANCE Opportunistic infections caused by species of the pathogenic yeast Cryptococcus lead to chronic meningoencephalitis and continue to ravage thousands of patients with HIV/AIDS. Despite receiving antifungal treatment, over 10% of patients develop recurrent disease. In this study, we collected isolates of Cryptococcus from cerebrospinal fluid specimens of 18 patients at the time of their diagnosis and when they relapsed several months later. We then sequenced and compared the genomic DNAs of each pair of initial and relapse isolates. We also tested the isolates for several key properties related to cryptococcal virulence as well as for their susceptibility to the antifungal drug fluconazole. These analyses revealed that the relapsing isolates manifested multiple genetic and chromosomal changes that affected a variety of genes implicated in the pathogenicity of Cryptococcus or resistance to fluconazole. This application of comparative genomics to serial clinical isolates provides a blueprint for identifying the mechanisms whereby pathogenic microbes adapt within patients to prolong disease.Yuan ChenRhys A. FarrerCharles GiamberardinoSharadha SakthikumarAlexander JonesTimothy YangJennifer L. TenorOmar WagihMarelize Van WykNelesh P. GovenderThomas G. MitchellAnastasia P. LitvintsevaChristina A. CuomoJohn R. PerfectAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 2 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Yuan Chen Rhys A. Farrer Charles Giamberardino Sharadha Sakthikumar Alexander Jones Timothy Yang Jennifer L. Tenor Omar Wagih Marelize Van Wyk Nelesh P. Govender Thomas G. Mitchell Anastasia P. Litvintseva Christina A. Cuomo John R. Perfect Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
description	ABSTRACT The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and relapse isolates may reveal evidence of determinative, microevolutionary changes within the host. Here, we analyzed serial isolates cultured from cerebrospinal fluid specimens of 18 South African patients with recurrent cryptococcal meningitis. The time between collection of the incident isolates and collection of the relapse isolates ranged from 124 days to 290 days, and the analyses revealed that, during this period within the patients, the isolates underwent several genetic and phenotypic changes. Considering the vast genetic diversity of cryptococcal isolates in sub-Saharan Africa, it was not surprising to find that the relapse isolates had acquired different genetic and correlative phenotypic changes. They exhibited various mechanisms for enhancing virulence, such as growth at 39°C, adaptation to stress, and capsule production; a remarkable amplification of ERG11 at the native and unlinked locus may provide stable resistance to fluconazole. Our data provide a deeper understanding of the microevolution of Cryptococcus species under pressure from antifungal chemotherapy and host immune responses. This investigation clearly suggests a promising strategy to identify novel targets for improved diagnosis, therapy, and prognosis. IMPORTANCE Opportunistic infections caused by species of the pathogenic yeast Cryptococcus lead to chronic meningoencephalitis and continue to ravage thousands of patients with HIV/AIDS. Despite receiving antifungal treatment, over 10% of patients develop recurrent disease. In this study, we collected isolates of Cryptococcus from cerebrospinal fluid specimens of 18 patients at the time of their diagnosis and when they relapsed several months later. We then sequenced and compared the genomic DNAs of each pair of initial and relapse isolates. We also tested the isolates for several key properties related to cryptococcal virulence as well as for their susceptibility to the antifungal drug fluconazole. These analyses revealed that the relapsing isolates manifested multiple genetic and chromosomal changes that affected a variety of genes implicated in the pathogenicity of Cryptococcus or resistance to fluconazole. This application of comparative genomics to serial clinical isolates provides a blueprint for identifying the mechanisms whereby pathogenic microbes adapt within patients to prolong disease.
format	article
author	Yuan Chen Rhys A. Farrer Charles Giamberardino Sharadha Sakthikumar Alexander Jones Timothy Yang Jennifer L. Tenor Omar Wagih Marelize Van Wyk Nelesh P. Govender Thomas G. Mitchell Anastasia P. Litvintseva Christina A. Cuomo John R. Perfect
author_facet	Yuan Chen Rhys A. Farrer Charles Giamberardino Sharadha Sakthikumar Alexander Jones Timothy Yang Jennifer L. Tenor Omar Wagih Marelize Van Wyk Nelesh P. Govender Thomas G. Mitchell Anastasia P. Litvintseva Christina A. Cuomo John R. Perfect
author_sort	Yuan Chen
title	Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
title_short	Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
title_full	Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
title_fullStr	Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
title_full_unstemmed	Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>
title_sort	microevolution of serial clinical isolates of <italic toggle="yes">cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">c. gattii</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/b5c9bad0bd6a426ba1fe07c9374e5456
work_keys_str_mv	AT yuanchen microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT rhysafarrer microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT charlesgiamberardino microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT sharadhasakthikumar microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT alexanderjones microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT timothyyang microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT jenniferltenor microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT omarwagih microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT marelizevanwyk microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT neleshpgovender microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT thomasgmitchell microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT anastasiaplitvintseva microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT christinaacuomo microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic AT johnrperfect microevolutionofserialclinicalisolatesofitalictoggleyescryptococcusneoformansitalicvaritalictoggleyesgrubiiitalicanditalictoggleyescgattiiitalic
_version_	1718427421537992704

Microevolution of Serial Clinical Isolates of <italic toggle="yes">Cryptococcus neoformans</italic> var. <italic toggle="yes">grubii</italic> and <italic toggle="yes">C. gattii</italic>

Ejemplares similares