Individual variations in immune status and function shape responses to infection and contribute to disease severity and outcome. Infections with West Nile virus can be asymptomatic or severe, even leading to death, and no effective therapies or vaccines are available. Thus, identifying molecular signatures of immunity and phenotypes of susceptibility is essential to guide development of improved diagnostics, therapeutic interventions and future vaccines. We propose studies with a coordinated Systems approach for investigation of stratified subjects with West Nile viral infections to define how components of the immune response contribute to divergent outcomes. We will employ recent advances in high-throughput and high-resolution technology to profile individual immune responses in order to identify the molecular signatures defining divergent responses to West Nile virus infections. We will use shared platforms such as CyTOF, metabolomics, and innovative nanowell cytometry linked to single cell RNA-seq to provide insight into the immune responses to WNV. Our coordinated in-depth systems analysis includes for the first time the phenotype and functionality of neutrophils, platelets, and metabolomics in divergent clinical outcomes. Through integrating multiple immune components, we will define response profiles that correlate with successful outcome of infection. Strengths of our proposal are the well characterized clinical populations, the coordinated in-depth interrogation of multiple cell types and responses, the experienced and coordinated research team, the interrogation and integration of multiple variables that influence immune responses, and established HIPC consortium networks.

Public Health Relevance

Infections with the flavivirus West Nile virus can asymptomatic or severe, even leading to death, and it remains unknown how components of the immune response contribute to divergent clinical outcomes. We will employ recent advances in high-resolution technology with a coordinated Systems approach to identify the molecular signatures defining divergent responses to West Nile virus infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Yale University
New Haven
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Ordovas-Montanes, Jose; Dwyer, Daniel F; Nyquist, Sarah K et al. (2018) Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560:649-654
Mead, Benjamin E; Ordovas-Montanes, Jose; Braun, Alexandra P et al. (2018) Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types. BMC Biol 16:62
Murray, Kristy O; Nolan, Melissa S; Ronca, Shannon E et al. (2018) The Neurocognitive and MRI Outcomes of West Nile Virus Infection: Preliminary Analysis Using an External Control Group. Front Neurol 9:111
Molony, Ryan D; Malawista, Anna; Montgomery, Ruth R (2018) Reduced dynamic range of antiviral innate immune responses in aging. Exp Gerontol 107:130-135
Martin-Gayo, Enrique; Cole, Michael B; Kolb, Kellie E et al. (2018) A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers. Genome Biol 19:10
Wang, Xiaomei; Malawista, Anna; Qian, Feng et al. (2018) Age-related changes in expression and signaling of TAM receptor inflammatory regulators in monocytes. Oncotarget 9:9572-9580
Cahill, Megan E; Conley, Samantha; DeWan, Andrew T et al. (2018) Identification of genetic variants associated with dengue or West Nile virus disease: a systematic review and meta-analysis. BMC Infect Dis 18:282
van Dijk, David; Sharma, Roshan; Nainys, Juozas et al. (2018) Recovering Gene Interactions from Single-Cell Data Using Data Diffusion. Cell 174:716-729.e27
Avey, Stefan; Mohanty, Subhasis; Wilson, Jean et al. (2017) Multiple network-constrained regressions expand insights into influenza vaccination responses. Bioinformatics 33:i208-i216
Cahill, Megan E; Yao, Yi; Nock, David et al. (2017) West Nile Virus Seroprevalence, Connecticut, USA, 2000-2014. Emerg Infect Dis 23:708-710

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