Rapid advances in genomic technologies are providing infectious disease researchers an unprecedented capability to study, at a genetic level, the viruses that cause disease and their interactions with infected hosts. The Broad Institute has led many technical and analytical advances that have enabled the genomic revolution and is one of the largest genome centers in the world. Our microbial genomics group has developed research programs in numerous viruses and has already sequenced over 6,500 viral strains from around the world. By leveraging the capacity and resources we have built in viral sequencing, as well as our field efforts and collaborations over the last decade, we will investigate three of the world's most important emerging infectious pathogens: Lassa Virus (LASV) and Dengue Virus (DENV), both Category A agents, and West Nile Virus (WNV), a Category B agent. These pathogens are notable for the high mortality, widespread disease and public health importance (in the US and elsewhere) they represent. Understanding how these small RNA viruses rapidly adapt to and escape from host selection pressures, including adaptive immune responses, is key to the design of viral diagnostics, vaccines and therapeutic drugs. Through our own efforts and through collaborations with clinicians and researchers, we have access to many important clinical and field samples that enable us to study not only viral evolution and spread within different geographic locations (Africa, South America and North America), but also viral adaptation within infected individuals. Rich collections of sample-associated metadata allow us to correlate viral genotype with disease severity and clinical outcome. Use of robust animal models of infection that recapitulate human disease progression will generate important insights into the pathology of LASV, DENV and WNV. Given the enzootic life cycle of these viruses, we are also investigating viral evolution and transmission within their natural hosts, which Include rodents, birds and mosquitos. Finally, we will take advantage of our existing global sample collection sites to investigate samples from patients who present symptoms similar to those caused by our diseases of study, but whose diagnoses remain unknown (FUOs, Fevers of Unknown Origin). Through these efforts we expect to better understand viral emergence and adaptation on a geographic scale as well as through the viral life cycle, from natural reservoirs to human infections. Detailed examination of viral diversity from field and clinical samples will provide remarkable insight into the dynamics of evolution and adaptation that are required for these viruses to emerge from isolated outbreaks to endemic disease with increasing health burdens worldwide.

Public Health Relevance

We aim to better understand viral emergence and adaptation on a geographic scale as well as through the viral life cycle, from natural reservoirs to human infections, of three of the world's most important emerging infectious pathogens: Lassa Virus (LASV), Dengue Virus (DENV), and West Nile Virus (WNV). Detailed examination of viral diversity from field and clinical samples will provide unprecedented insight into the dynamics of evolution and adaptation of these viruses, and provide critical information for the design of diagnostics, vaccines and therapeutic drugs. Through our efforts, we can further uncover viral causes of fever among patients whose diagnoses are currently unknown.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI110818-04
Application #
9252371
Study Section
Special Emphasis Panel (ZAI1-EC-M)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
4
Fiscal Year
2017
Total Cost
$799,722
Indirect Cost
$304,309
Name
Broad Institute, Inc.
Department
Type
Research Institutes
DUNS #
623544785
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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
Brennan-Krohn, Thea; Pironti, Alejandro; Kirby, James E (2018) Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae. Antimicrob Agents Chemother 62:
Messina, Julia A; Wolfe, Cameron R; Hemmersbach-Miller, Marion et al. (2018) Genomic characterization of recurrent mold infections in thoracic transplant recipients. Transpl Infect Dis 20:e12935
Schaffner, Stephen F; Taylor, Aimee R; Wong, Wesley et al. (2018) hmmIBD: software to infer pairwise identity by descent between haploid genotypes. Malar J 17:196
Farrer, Rhys A; Ford, Christopher B; Rhodes, Johanna et al. (2018) Transcriptional Heterogeneity of Cryptococcus gattii VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways. mSphere 3:
Myhrvold, Cameron; Freije, Catherine A; Gootenberg, Jonathan S et al. (2018) Field-deployable viral diagnostics using CRISPR-Cas13. Science 360:444-448
Cuomo, Christina A; Rhodes, Johanna; Desjardins, Christopher A (2018) Advances in Cryptococcus genomics: insights into the evolution of pathogenesis. Mem Inst Oswaldo Cruz 113:e170473

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