Genomic predisposition and adaptation ito virulence in aspergillosis

Author:

S Gago1, A Khateb1, I Gut2, W Nierman3, DW Denning1, M Bromley1, P Bowyer1

Author address:

1Manchester Fungal Infection Group, University of Manchester, Manchester, UK
3Genomic Centre for Infectious Disease, J Craig Ventner Institute, Rockville, MA, USA

Full conference title:

9th Advances Against Aspergillosis

Date: 26 February 2020

Abstract:

Purpose: The genomes of isolates of Aspergillus fumigatus are complex and display a high degree of hetergeneity. Few studies have addressed pathogenicity in chronic pulmonary aspergillosis (CPA) and allergic pulmonary aspergillosis (ABPA) and little is known regarding genome variants that could predispose isolates to pathogenesis. This study aims to discover whether particular genomic features predispose isolates to pathogenicity or to particular types of aspergillosis and whether genome plasticity plays a role in virulence.

Methods: Genome sequences from 171 clinical and environmental isolates were obtained. Isolates werre obtained from public datasets and through sequencig of isolates from the Manchester Mycology Lab, including isolates from ABPA, CPA and CPA -aspergillomas. Isolates were phenotyped for drug resistance, disease and growth morphology. Genomes were analysed to determine gene copy number, single nucleotide polymprphisms and deletions using GATK, PLINK, R packages for genotype and phenotype association and bespoke scripts. Phylogenies were estimated using RaxML of whole genome vcf files and ROADTRIPS to assess lineage specific contributions. Genes arnd regions identified from bioinformatic analysis were tested by gene knockout and phenotyped for secondary metabolite production (HPLC), pathogenicity, epithelial cell damage and detachment, induction of cytokines, phagocytic survival and ability to form in-vitro aspergilloma.

Results: A wide range of genetic variants were discovered including 1.2m SNPs, 7 major chromosome duplications, 7 deletions (>10KB) and a range of probable translocation events. Large scale genomic changes were observed primarily in CPA and CPA-aspergilloma isolates. These included large scale genome duplications related to drug resistance and small scale deletions related to pathogenicity and epithelial damage phenotypes. SNPs leading to cryptic peroxisomal targeting via translational readthrough were strongly associated with disease. Finally clusters of genes that displayed hetergeneity across A. fumigatus populations were found to predispose such isolates to pathogenicity for certain aspergillosis disease types, particularly CPA.

Conclusion: Genome analysis has revealed important predisposing factors in A. fumigatus genomes that condition such isolates for particular forms of aspergillosis. Additionally analysis of genome changes statistically related to drug resistance and disease reveals several new mechanisms for drug resistance and pathogenicity in this fungus.

Abstract Number: 146

Link to conference website:

Link Conference abstract: 

AAAM 2020

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