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Single nucleotide variations account for strain specific virulence changes in Cryptococcus neoformans

单核苷酸变异解释了新型隐球菌菌株特异性毒力的变化

基本信息

批准号：
10207436
负责人：
Katrina M Jackson
金额：
$ 3.24万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-26 至 2022-08-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207436
关键词：
Acquired Immunodeficiency Syndrome Adult Africa South of the Sahara Alleles Bioinformatics Biological Biological Process Biological Testing Brain Central Nervous System Infections Cessation of life Chromosome Structures Chromosomes Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus neoformans Data Diagnosis Diagnostic Diagnostic Procedure Disease Disease Outcome Exhibits Failure Gene Deletion Gene Exchanges Genes Genetic Genome Genomics Genotype Goals Human Immune response Immune system Impairment In Vitro Individual Infection Lead Learning Meningitis Mutation Neurologic Nucleotides Organism Outcome Pathogenesis Patient-Focused Outcomes Patients Phenotype Play Population Production Proteins Research Research Personnel Resolution Role Single Nucleotide Polymorphism Structure Testing Treatment outcome Tuberculosis Uganda Variant Virulence Virulence Factors Virulent base clinically relevant gene function genetic variant genome wide association study human disease improved in silico in vivo innovation insertion/deletion mutation low and middle-income countries microorganism mortality mouse model novel optimal treatments pathogen pathogenic fungus skills success targeted treatment tool translational study whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Cryptococcal meningitis (CM) is a severe central nervous system (CNS) infection caused by the fungal pathogen Cryptococcus neoformans, primarily in people with compromised immune systems. CM kills 181,000 people annually, with the largest burden on AIDS patients. It is the second most common killer of AIDS patients in sub-Saharan Africa, behind only tuberculosis. Both the treatment and diagnosis of CM is complicated by a well-documented variability in disease presentation. Changes in patient outcome have been associated, in part, with the genotype of C. neoformans. We performed a preliminary genome wide association study (GWAS) on 40 whole genomes of clinical isolates with associated patient data. The GWAS revealed an association between single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELs) in C. neoformans genes and patient outcome. We deleted a sub-set of these genes and showed they play a previously uncharacterized role in virulence. Furthermore, there is a documented association between structural variation in the C. neoformans genome and patient outcome. This proposal will test the hypothesis that individual nucleotide variations cause changes in patient disease presentation. Aim 1 will identify SNPs/INDELs in a large population of C. neoformans clinical isolates by using amplicon sequencing and will use long-read sequencing to characterize structural variants in the clinical isolates. We will compare these data to patient outcome to identify clinically relevant genomic variants. Aim 2 will determine the role of the nucleotide variations in a biological context by exchanging gene alleles in virulent or avirulent genetic backgrounds and then analyzing changes in pathogenesis. Aim 2 will define the biological function of the observed genomic differences through characterization of novel genes identified in the preliminary GWAS analysis. Finally, we will introduce single nucleotide variations into the reference gene alleles using CRISPR to define the impact of single genetic changes. The proposed research is innovative in that it is the first to compare single nucleotide polymorphisms in C. neoformans and differences in patient outcome. The proposed research will 1) determine the role of SNP/INDELs on C. neoformans phenotype; 2) identify unknown virulence factors; and 3) build a diagnostic method for identifying the infecting C. neoformans strain, leading to targeted therapy and improved patient survival.

项目总结/文摘