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Neurotropism and Neurotoxicity Comparison among Retrograde Viral Tracers and Their Combinational Application in High-order Circuit Tracing

ABSTRACT: Here, we demonstrated the neurotropism of different retrograde viral tracers are distinct through parallel comparison of multi-synaptic and mono-synaptic tracers in circuit tracing. By virture of their distinct tropism, we reconstructed more comprehensive LHA input circuit map. Notably, exogenous expression of TVA receptor in rabies virus (RV) resistant neurons can enable the infection of EnVA-pseudotyped RV. The potential viral receptor candidates attributing to neurotropism were analyzed by single cell sequencing. Further, we systematically compared neurotoxicity of glycoprotein-deleted RV and rAAV2-retro by RNAseq and immunohistochemistry. Finally, we demonstrated a proof-of-concept strategy for high-order circuit tracing by combining different viral tracers.

ORGANISM(S): Mus musculus

PROVIDER: GSE115865 | GEO | 2018/06/23

REPOSITORIES: GEO

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Project description:Rhinoviruses (RVs) are major instigators of acute exacerbations of asthma, COPD and other respiratory diseases. RVs are categorized into three species (RV-A, RV-B, and RV-C), which comprise more than 160 serotypes, making it difficult to develop an effective vaccine. Currently no effective treatment for RV infection is available. Pulmonary surfactant is an extracellular complex of lipids and proteins that plays a central role in regulating innate immunity in the lung. The minor pulmonary surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), are potent regulators of inflammatory processes, and exert antiviral activity against respiratory syncytial virus (RSV) and influenza A viruses (IAV). In the current study, we examined the potencies of POPG and PI against rhinovirus A16 (RV-A16) in primary human airway epithelial cells (AECs) differentiated at an air-liquid interface (ALI). After AECs were infected with RV-A16, PI reduced viral RNA copy number by 80% and downregulated (55-65%) expression of antiviral genes (MDA5, IRF7 and IFN-lambda). In contrast, POPG only slightly decreased MDA5 (24%) and IRF7 (11%) gene expression but did not inhibit IFN-lambda gene expression or RV-A16 replication in AECs. However, both POPG and PI inhibited (50-80%) IL6 and CXCL11 gene expression and protein secretion. PI treatment dramatically attenuated global gene expression changes induced by RV-A16 infection in AECs. Cell type enrichment analysis of viral regulated genes opposed by PI treatment revealed that PI inhibited viral induction of goblet cell metaplasia and virus-induced downregulation of ciliated, club, and ionocyte cell types. Notably, PI treament altered the ability of RV-A16 to regulate expression of some phosphatidylinositol 4-kinase (PI4K), acyl-CoA binding domain containing (ACBD) and low density lipoprotein receptor (LDLR) genes that play critical roles in the formation and functioning of replication organelles (ROs) required for RV replication in host cells. These data suggest PI can be used as a potent, non-toxic antiviral agent for RV infection prophylaxis and treatment.

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Neurotropism and Neurotoxicity Comparison among Retrograde Viral Tracers and Their Combinational Application in High-order Circuit Tracing

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