Single-cell RNA transcriptome analysis of murine male and female forebrain tissue after recovery from West Nile virus encephalitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE212199 | GEO | 2022/09/01
REPOSITORIES: GEO
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Project description:Greater than 50% of patients who survive neuroinvasive West Nile virus (WNV), a mosquito-borne, positive-sense strand flavivirus, exhibit cognitive sequelae including memory impairments which may last several years. High survival rates from WNV neuroinvasive disease (WNND) (>90%) have led to hundreds to thousands of cases of WNV-mediated neurologic impairment accruing annually, yet underlying mechanisms responsible for these impairments have not been investigated. Here, we established a novel murine model of recovery from WNND in which intracranial inoculation of a mutant WNV (WNV-NS5-E218A) leads to rates of survival and cognitive dysfunction that mirror human WNND. WNV-NS5-E218A-recovered mice exhibit impaired spatial learning and persistently phagocytic microglia without significant loss of hippocampal neurons or brain volume. Whole transcriptome analysis of hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning was performed in order to identify target pathways and molecules underlying cognitive impairments during WNND recovery. Total RNA obtained from isolated murine hippocampus at 25 days post-mock or WNV-NS5-E218A intracranial infection.
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Project description:Greater than 50% of patients who survive neuroinvasive West Nile virus (WNV), a mosquito-borne, positive-sense strand flavivirus, exhibit cognitive sequelae including memory impairments which may last several years. High survival rates from WNV neuroinvasive disease (WNND) (>90%) have led to hundreds to thousands of cases of WNV-mediated neurologic impairment accruing annually, yet underlying mechanisms responsible for these impairments have not been investigated. Here, we established a novel murine model of recovery from WNND in which intracranial inoculation of a mutant WNV (WNV-NS5-E218A) leads to rates of survival and cognitive dysfunction that mirror human WNND. WNV-NS5-E218A-recovered mice exhibit impaired spatial learning and persistently phagocytic microglia without significant loss of hippocampal neurons or brain volume. Whole transcriptome analysis of hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning was performed in order to identify target pathways and molecules underlying cognitive impairments during WNND recovery.
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Project description:West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Recent studies in humans have found that dysfunctional T cell responses strongly correlate with development of severe WNV neuroinvasive disease. However, the contributions of human dendritic cells (DCs) in priming WNV-specific T cell immunity remains poorly understood. Here, we demonstrate that human monocyte derived DCs (moDCs) support productive viral replication following infection with a pathogenic strain of WNV. Antiviral effector gene transcription was strongly induced during the log-phase viral growth, while secretion of type I interferons (IFN) occurred with delayed kinetics. Activation of RIG-I like receptor (RLR) or type I IFN signaling prior to log-phase viral growth significantly diminished viral replication, suggesting that early activation of antiviral programs can block WNV infection. In contrast to the induction of antiviral responses, WNV infection did not promote transcription or secretion of pro-inflammatory (IL-6, GM-CSF, CCL3, CCL5, CXCL9) or T cell modulatory cytokines (IL-4, IL-12, IL-15). There was also minimal induction of molecules associated with antigen presentation and T cell priming, including the co-stimulatory molecules CD80, CD86, and CD40. Functionally, WNV-infected moDCs dampened allogenic CD4 and CD8 T cell activation and proliferation. Combined, we propose a model where WNV subverts human DC activation to compromise priming of WNV-specific T cell immunity.
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