The early involvement of CNS-draining lymphatics and host response to West Nile virus infection
- Author/Creator:
- O'Neal, Troy Justin, author
- Publication/Creation:
- Ann Arbor : ProQuest Dissertations & Theses, 2020
- Resource Type:
- Book
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Additional/Related Title Information
- Full Title:
- The early involvement of CNS-draining lymphatics and host response to West Nile virus infection / Troy Justin O'Neal
Related Names
- Additional Author/Creators:
- Suthar, Mehul, degree supervisor
Emory University. Graduate Division of Biological and Biomedical Sciences, degree granting institution
Subjects/Genre
Description/Summary
- Summary:
- West Nile virus (WNV) is a mosquito-borne flavivirus of global importance, which can result in neuroinvasive infection leading to encephalitis, prolonged neurological dysfunction or death. The early induction of the host response and efficient CD8+ T cell responses are both required for protection. We found that viral RNA and activated conventional dendritic cells (cDCs) accumulated in the meninges and CNS-draining lymph nodes (LNs) prior to neuroinvasion. Furthermore, WNV-specific CD8+ T cells accumulated in the CNS-draining LNs and the spleen with similar kinetics. WNV-specific CD8+ T cells from the spleen and brain exhibited dramatically different activation and inhibitory marker expression and cytokine production, whereas WNV-specific CD8+ T cells from the meninges and CNS-draining LNs displayed unique intermediate phenotypes. Notably, meningeal and brain WNV-specific CD8+ T cells produced both tumor necrosis factor (TNF)-α and interferon (IFN)-γ and had the highest fraction of cells expressing PD-1. CNS-localized WNV-specific CD8+ T cells were more efficient at controlling viral infection of cortical neurons than peripheral WNV-specific CD8+ T cells. These findings characterize the early involvement of CNS-draining lymphatics during WNV pathogenesis and indicate that anatomic localization influences CD8+ T cell programming during WNV infection. The type I IFN (IFN-I) response promotes induction of innate antiviral defenses, restricting early viral replication. We developed WNV- inclusive single-cell RNA sequencing (scRNA-seq), an approach to examine transcriptional heterogeneity in IFN-stimulated gene (ISG) induction and viral RNA abundance across single cells. We observed that only a small fraction of cells within the bulk population produced high levels of IFN-β transcript. Genes associated with the IFN- I response exhibited both high unimodal and bimodal variation. The majority of ISGs negatively correlated with viral RNA abundance, often displaying a sharp decline in expression for cells with high levels of viral RNA. WNV-inclusive scRNA-seq represents a robust approach for parallel single-cell transcriptomics and WNV RNA detection, which can be implemented in other systems to identify novel therapeutic targets or extend the resolution of in vivo studies to single infected cells.
- Language:
- English
- Language Note:
- English
- Physical Type/Description:
- 1 online resource (153 pages)
- General Note:
- Source of abstract: Dissertations Abstracts International, Volume: 81-08, Section: B.
Advisors: Suthar, Mehul ; Committee members: Arash Grakoui; Steven Bosinger; Jacob Kohlmeier; Bernardo Mainou.
Keywords: Host response; Single cell RNA sequencing; CNS lymphatics; Flavivirus; West Nile virus - Local Note:
- ProQuest digital dissertation copies of Emory dissertations may be downloaded free of charge by Emory faculty, students, and staff unless the author has chosen to embargo the work.
Additional Identifiers
- Catalog ID (MMSID):
- 9937181519902486
- ISBN:
- 9781392354162
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