Fungal pathogens have a significant and increasing impact on human health-, and the lack of effective treatments highlight the need for further study. This proposal will examine both major pathogens with large clinical impacts and recent cases of severe outbreaks of fungal infections. In the first aim, we will examine two large clinical cohorts of Cryptococcus neoformans, to define the genetic determinants of virulence and niche adaptation in the pathogen. We will also characterize pathogen gene expression at the primary site of severe infection, and both screen for and evaluate mutations that stabilize extra copies of chromosomes, a major mechanism of fungal drug resistance. In the second aim, we will examine three recent cases of fungal outbreaks in the US;isolates of Cryptococcus gattii and Fusarium spp will be sampled from clinical cases and the environment and sequenced to examine how environmental reservoirs differ from strains virulent in humans, similar to work in aim 1, and further monitor how one of these outbreaks spread over geography and time. Lastly in aim 3, we will examine the host and pathogen interface for C. albicans, a common commensal and the most common fungal pathogen, and other commonly observed Candida species infecting the primary innate immune cells involved in early Candida detection and response. We will use network analysis to identify host-pathogen hubs and to study how these networks evolve between strains and species differing in virulence and drug resistance. While these aims represent independent projects to examine fungal pathogenesis, each utilizes large-scale sequencing to extend and develop new paradigms for genomic analysis of fungal virulence.

Public Health Relevance

Fungal pathogens have a major impact on human health;the lack of effective antifungal therapies, the diversity of species infecting humans, and the emergence of new lineages or species represent major challenges to treatment. This proposal will examine clinical strains from major pathogens and recent fungal outbreaks to better determine the genetic basis of highly virulent strains and variation of such traits in the population. This work will provide an unprecedented whole-genome view into pathogens associated with

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI110818-01
Application #
8710822
Study Section
Special Emphasis Panel ()
Project Start
Project End
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$629,797
Indirect Cost
$229,221
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Diehl, William E; Lin, Aaron E; Grubaugh, Nathan D et al. (2016) Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic. Cell 167:1088-1098.e6
Colubri, Andres; Silver, Tom; Fradet, Terrence et al. (2016) Transforming Clinical Data into Actionable Prognosis Models: Machine-Learning Framework and Field-Deployable App to Predict Outcome of Ebola Patients. PLoS Negl Trop Dis 10:e0004549
Malinga, Lesibana A; Abeel, Thomas; Desjardins, Christopher A et al. (2016) Draft Genome Sequences of Two Extensively Drug-Resistant Strains of Mycobacterium tuberculosis Belonging to the Euro-American S Lineage. Genome Announc 4:
Issi, Luca; Farrer, Rhys A; Pastor, Kelly et al. (2016) Members of the Zinc Cluster Factor Family Alters Virulence in Candida albicans. Genetics :
Anderson, Matthew Z; Porman, Allison M; Wang, Na et al. (2016) A Multistate Toggle Switch Defines Fungal Cell Fates and Is Regulated by Synergistic Genetic Cues. PLoS Genet 12:e1006353
Colgrove, Robert C; Liu, Xueqiao; Griffiths, Anthony et al. (2016) History and genomic sequence analysis of the herpes simplex virus 1 KOS and KOS1.1 sub-strains. Virology 487:215-21
Grant, Sarah Schmidt; Wellington, Samantha; Kawate, Tomohiko et al. (2016) Baeyer-Villiger Monooxygenases EthA and MymA Are Required for Activation of Replicating and Non-replicating Mycobacterium tuberculosis Inhibitors. Cell Chem Biol 23:666-77
Tewhey, Ryan; Kotliar, Dylan; Park, Daniel S et al. (2016) Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay. Cell 165:1519-29
Zhang, Danfeng; Gomez, James E; Chien, Jung-Yien et al. (2016) Genomic analysis of the evolution of fluoroquinolone resistance in Mycobacterium tuberculosis prior to tuberculosis diagnosis. Antimicrob Agents Chemother :
Caballero, Ignacio S; Honko, Anna N; Gire, Stephen K et al. (2016) In vivo Ebola virus infection leads to a strong innate response in circulating immune cells. BMC Genomics 17:707

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