Interactions between Neuronal Innate Immune Pattern Recognition Receptor Pathways and Neurotropic Arboviruses: Host Measures, Viral Countermeasures, and Potential Therapeutics.

Neurotropic Arbovirus;Innate Immunology;Pattern Recognition Receptor Siganling;Western Equine Encephalitis Virus;Small Molecule Inhibitior High Throughput Screen;Microbiology and Immunology;Health Sciences;Microbiology & Immunology

Peltier, Daniel C.Swanson, Michele S. ;

University of Michigan

关键词: Neurotropic Arbovirus;    Innate Immunology;    Pattern Recognition Receptor Siganling;    Western Equine Encephalitis Virus;    Small Molecule Inhibitior High Throughput Screen;    Microbiology and Immunology;    Health Sciences;    Microbiology & Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/91521/peltierd_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Neurotropic arboviruses are a group of pathogens capable of causing severe and fatal central nervous system infections for which there are few effective treatments or vaccines.The extent of neurotropic arbovirus-mediated destruction of central nervous system neurons is often an important determinant in the severity and clinical outcome after infection.Early cellular innate immune responses mediated by pattern recognition receptors (PRRs) are often vital for effective pathogen control, and an effective neuronal innate immune response may be crucial to prevent the essentially irreversible loss of critical central nervous system neurons by neurotropic arboviruses.The work presented here describes efforts to preserve neurotropic arbovirus-infected neurons by: a) studying the interactions between neurotropic arboviruses and neuronal PRR pathways in order to indentify novel targets for future therapeutics, and b) identifying potential anti-neurotropic arbovirus medications which target viral replication. Innate PRR pathways function in both a cell and pathogen-specific manner.However, relatively little is known about the induction and regulation of neuronal PRR signaling.Therefore, I assessed PRR pathway expression and function in neurons and found that neurons possess functional PRR pathways mediated by select receptors and signaling molecules which activate the downstream transcription factors NFkB and IRF3 resulting in the production of genes with putative antiviral activity.Next, I characterized how neuronal PRR pathways interact with neurotropic arboviruses using western equine encephalitis virus (WEEV) as a model neurotropic arbovirus.From these studies I concluded that IRF3 mediates a neuron-protective response to WEEV; however, this response was independent of type-I IFN signaling, which possesses potent antiviral activity and is canonically activated downstream of IRF3 in alternate cell types.Importantly, WEEV inhibited neuronal PRR-mediated induction of antiviral type-I interferons, and this inhibitory capacity was mapped to the WEEV capsid protein.These data indicated that neuronal PRR pathways may be important determinants in neurotropic arbovirus pathogenesis and that neuronal PRR pathways and viral countermeasures to them may be exploited to develop anti-neurotropic arboviral treatments.Finally, I identified a novel class of small molecules which inhibit WEEV replication, protect neuronal cells from WEEV-induced cell death, and may be a useful component of future anti-neurotropic arbovirus therapies.