Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam

Jeremy N. Day, Seet Qihui, Lam Tuan Thanh, Phan Hai Trieu, Anh Duong Van, Nha Hoang Thu, Tran Thi Hong Chau, Nguyen P.H. Lan, Nguyen Van Vinh Chau, Philip M. Ashton, Guy E. Thwaites, Maciej F. Boni, Marcel Wolbers, Niranjan Nagarajan, Patrick B.O. Tan, Stephen Baker

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher’s exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

Original languageEnglish (US)
Article numbere0005628
JournalPLoS neglected tropical diseases
Volume11
Issue number6
DOIs
StatePublished - Jun 14 2017

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Cryptococcus neoformans
Vietnam
Genomics
Meningitis
HIV
Cryptococcal Meningitis
Genome
Infection
Phenotype
Pyroglutamate Hydrolase
Viral Tropism
RNA Helicases
Dioxygenases
Membrane Transport Proteins
Taurine
Zinc Fingers
Lymphocyte Count
Hematologic Tests
Virulence
Survivors

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Day, Jeremy N. ; Qihui, Seet ; Thanh, Lam Tuan ; Trieu, Phan Hai ; Van, Anh Duong ; Thu, Nha Hoang ; Chau, Tran Thi Hong ; Lan, Nguyen P.H. ; Chau, Nguyen Van Vinh ; Ashton, Philip M. ; Thwaites, Guy E. ; Boni, Maciej F. ; Wolbers, Marcel ; Nagarajan, Niranjan ; Tan, Patrick B.O. ; Baker, Stephen. / Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam. In: PLoS neglected tropical diseases. 2017 ; Vol. 11, No. 6.
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abstract = "The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11{\%} vs. 4{\%}, p = 0.05 Fisher’s exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7{\%} (40/55) in ST5 infections versus 57.1{\%} (52/91) non-ST5 infections (OR 2.11, 95{\%}CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99{\%} nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.",
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Day, JN, Qihui, S, Thanh, LT, Trieu, PH, Van, AD, Thu, NH, Chau, TTH, Lan, NPH, Chau, NVV, Ashton, PM, Thwaites, GE, Boni, MF, Wolbers, M, Nagarajan, N, Tan, PBO & Baker, S 2017, 'Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam', PLoS neglected tropical diseases, vol. 11, no. 6, e0005628. https://doi.org/10.1371/journal.pntd.0005628

Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam. / Day, Jeremy N.; Qihui, Seet; Thanh, Lam Tuan; Trieu, Phan Hai; Van, Anh Duong; Thu, Nha Hoang; Chau, Tran Thi Hong; Lan, Nguyen P.H.; Chau, Nguyen Van Vinh; Ashton, Philip M.; Thwaites, Guy E.; Boni, Maciej F.; Wolbers, Marcel; Nagarajan, Niranjan; Tan, Patrick B.O.; Baker, Stephen.

In: PLoS neglected tropical diseases, Vol. 11, No. 6, e0005628, 14.06.2017.

Research output: Contribution to journalArticle

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T1 - Comparative genomics of Cryptococcus neoformans var. grubii associated with meningitis in HIV infected and uninfected patients in Vietnam

AU - Day, Jeremy N.

AU - Qihui, Seet

AU - Thanh, Lam Tuan

AU - Trieu, Phan Hai

AU - Van, Anh Duong

AU - Thu, Nha Hoang

AU - Chau, Tran Thi Hong

AU - Lan, Nguyen P.H.

AU - Chau, Nguyen Van Vinh

AU - Ashton, Philip M.

AU - Thwaites, Guy E.

AU - Boni, Maciej F.

AU - Wolbers, Marcel

AU - Nagarajan, Niranjan

AU - Tan, Patrick B.O.

AU - Baker, Stephen

PY - 2017/6/14

Y1 - 2017/6/14

N2 - The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher’s exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

AB - The vast burden of cryptococcal meningitis occurs in immunosuppressed patients, driven by HIV, and is caused by Cryptococcus neoformans var. grubii. We previously reported cryptococcal meningitis in Vietnam arising atypically in HIV uninfected, apparently immunocompetent patients, caused by a single amplified fragment length polymorphism (AFLP) cluster of C. neoformans var. grubii (VNIγ). This variant was less common in HIV infected individuals; it remains unclear why this lineage is associated with apparently immunocompetent patients. To study this host tropism we aimed to further our understanding of clinical phenotype and genomic variation within Vietnamese C. neoformans var. grubii. After performing MLST on C. neoformans clinical isolates we identified 14 sequence types (STs); ST5 correlated with the VNIγ cluster. We next compared clinical phenotype by lineage and found HIV infected patients with cryptococcal meningitis caused by ST5 organisms were significantly more likely to have lymphadenopathy (11% vs. 4%, p = 0.05 Fisher’s exact test) and higher blood lymphocyte count (median 0.76 versus 0.55 X109cells/L, p = 0.001, Kruskal-Wallis test). Furthermore, survivors of ST5 infections had evidence of worse disability outcomes at 70 days (72.7% (40/55) in ST5 infections versus 57.1% (52/91) non-ST5 infections (OR 2.11, 95%CI 1.01 to 4.41), p = 0.046). To further investigate the relationship between strain and disease phenotype we performed genome sequencing on eight Vietnamese C. neoformans var. grubii. Eight genome assemblies exhibited >99% nucleotide sequence identity and we identified 165 kbp of lineage specific to Vietnamese isolates. ST5 genomes harbored several strain specific regions, incorporating 19 annotated coding sequences and eight hypothetical proteins. These regions included a phenolic acid decarboxylase, a DEAD-box ATP-dependent RNA helicase 26, oxoprolinases, a taurine catabolism dioxygenase, a zinc finger protein, membrane transport proteins and various drug transporters. Our work outlines the complexity of genomic pathogenicity in cryptococcal infections and identifies a number of gene candidates that may aid the disaggregation of the pathways associated with the pathogenesis of Cryptococcus neoformans var. grubii.

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