Ensuring a world safe from microbial threats remains a pressing challenge. However, significant gaps remain in our understanding of viral diseases. This proposal employs genomics to address these three major needs: Genomic detection and epidemiology of emerging viral threats in humans and vectors?. For emerging viruses, such as Lassa, Ebola, Zika, Powassan, and other NIAID Category A-C Priority Pathogens, the natural prevalence, evolution, genetic diversity, and transmission among and between humans and zoonotic hosts are not well characterized, which threatens our ability to prepare for and even identify human cases when they occur. Pathogen genomics provides critical public health insight into the movement of viral threats. In partnership with established clinical, public health, and academic collaborators in West Africa and Massachusetts, this project will sequence viruses both human patients and zoonotic reservoirs (African rodents, American ticks and mosquitoes), publicly distribute genomic and metagenomic datasets, and rapidly deliver analyses relevant to the evolution, epidemiology and ecology of these viruses, with a focus on insights that may inform the ongoing development work of diagnostics, therapeutics, and other intervention strategies. Tissue-specific and single-cell characterizations of host response and viral dynamics during viral hemorrhagic fever infection?. Viral hemorrhagic fevers (VHFs) like Ebola and Lassa are highly fatal, but how the molecular and cellular host response mechanisms differ between fatal and non-fatal cases is poorly understood. In partnership with NIAID?s Integrated Research Facility in Frederick, MD (BSL-4), this project will sequence ?in vivo? VHF infections in animal model organisms, simultaneously profiling both the host transcriptional response and viral replication and evolution within different host tissues, and utilizing single-cell RNA-seq approaches to interrogate individual host PBMC types. This will provide a new understanding of cell-specific host response to VHF infections, with insights into the differing mechanisms behind fatality and recovery and inform the development of countermeasures for VHFs. Systematic discovery of viral antigens using thousands of rationally designed oligonucleotides?. For most viral threats, our ability to respond is hampered by a lack of systematic, high-throughput methods that evaluate and inform the development of therapeutics and vaccines. Although cytotoxic T lymphocytes can afford protection against a wide range of viral antigens, there has not been a systematic investigation of all possible immunogenic peptides. Utilizing a ?systems virology? approach, we will design, create, evaluate, and test a large synthetic library of oligos that span large portions of hundreds of human viral pathogens and produce novel candidate targets for vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI110818-07
Application #
9919482
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Broad Institute, Inc.
Department
Type
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Muñoz, José F; Gade, Lalitha; Chow, Nancy A et al. (2018) Genomic insights into multidrug-resistance, mating and virulence in Candida auris and related emerging species. Nat Commun 9:5346
Lebreton, François; Valentino, Michael D; Schaufler, Katharina et al. (2018) Transferable vancomycin resistance in clade B commensal-type Enterococcus faecium. J Antimicrob Chemother 73:1479-1486
Yadav, Vikas; Sun, Sheng; Billmyre, R Blake et al. (2018) RNAi is a critical determinant of centromere evolution in closely related fungi. Proc Natl Acad Sci U S A 115:3108-3113
Hommel, Benjamin; Mukaremera, Liliane; Cordero, Radames J B et al. (2018) Titan cells formation in Cryptococcus neoformans is finely tuned by environmental conditions and modulated by positive and negative genetic regulators. PLoS Pathog 14:e1006982
Muñoz, José F; McEwen, Juan G; Clay, Oliver K et al. (2018) Genome analysis reveals evolutionary mechanisms of adaptation in systemic dimorphic fungi. Sci Rep 8:4473
Zhang, Wei; Lun, Shichun; Wang, Shu-Huan et al. (2018) Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors Against Mycobacterium Tuberculosis. J Med Chem :
Rhodes, Johanna; Abdolrasouli, Alireza; Farrer, Rhys A et al. (2018) Genomic epidemiology of the UK outbreak of the emerging human fungal pathogen Candida auris. Emerg Microbes Infect 7:43
Sephton-Clark, Poppy C S; Muñoz, Jose F; Ballou, Elizabeth R et al. (2018) Pathways of Pathogenicity: Transcriptional Stages of Germination in the Fatal Fungal Pathogen Rhizopus delemar. mSphere 3:
Ene, Iuliana V; Farrer, Rhys A; Hirakawa, Matthew P et al. (2018) Global analysis of mutations driving microevolution of a heterozygous diploid fungal pathogen. Proc Natl Acad Sci U S A 115:E8688-E8697
Siddle, Katherine J; Eromon, Philomena; Barnes, Kayla G et al. (2018) Genomic Analysis of Lassa Virus during an Increase in Cases in Nigeria in 2018. N Engl J Med 379:1745-1753

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