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RIPK signaling in neurons during West Nile virus infection drives chemokine expression and subsequent recruitment of inflammatory cells into the infected CNS. 

(see Daniels et al, Cell, 2017)

RIPK3 signaling in the coordination of neuroinflammation

 

A major goal of our work is identifying specialized roles for programmed cell death (PCD) signaling in the CNS. We and others have previously uncovered neuron-specific, non-canonical functions for a pathway that normally promotes necroptosis, an inflammatory form of PCD mediated by the protein RIPK3. This work showed that neurons have evolved alternative, cell death-independent functions for RIPK3 in response to viral infection. Instead of inducing necroptosis, neuronal RIPK3 signaling drives a specialized inflammatory gene transcriptional program that promotes an immune response without killing the host neuron. These findings suggest that the signaling axis promoting immunogenic cell death is highly specialized in nervous tissue, though the mechanisms that govern this specialization remain to be discovered.

An important question emanating from this work is whether the death-independent RIPK3-mediated transcriptional response operates in non-neuronal CNS cell types, including astrocytes. We have used advanced mouse genetic tools and primary culture systems to show that astrocytes are also resistant to necroptosis, instead exhibiting a RIPK3-dependent transcriptional program that controls their activation state. This regulation of astrocyte activation state, in turn, influences major astrocyte functions, including neurotoxic activity and the regulation of leukocyte recruitment into the CNS. We are now exploring how the astrocytic RIPK3 pathway is engaged during sterile neuroinflammatory states, such as Parkinson’s disease, as well as during viral encephalitis. Going forward, we hope to define how astrocytic RIPK3 signaling shapes neuroinflammatory disease pathogenesis in diverse CNS disease states, using a variety of cutting-edge approaches, including intersectional mouse genetics, scRNA sequencing, and unbiased proteomics.

We study how resident cells of the central nervous system coordinate specialized immune responses to infection and injury.

 

The Daniels lab is pursuing diverse projects in the area of neuro-immune cross talk. We are particularly focused on understanding the intrinsic immune activities of neural cells, including neurons and astrocytes, with the goal of defining their contributions to immune homeostasis, pathogen clearance, and immunopathology during CNS disease states.

Innate immune regulation of neural development and neurotransmission

Additional projects in the lab focus on examining the direct neurologic impact of viral infection, including alterations to neurodevelopment and host behavior. For example, we are pursuing a collaborative project with Dr. Alexander Kusnecov to assess the impact of maternal ZIKV infection during late pregnancy on brain development and behavioral abnormalities in offspring. To date, studies of maternal ZIKV infection have focused heavily on severe congenital abnormalities, including microcephaly, which result from vertical transmission early in gestation. However, the majority of children born to ZIKV-infected mothers do not present with severe developmental defects, though the long-term impacts of exposure to maternal anti-ZIKV immune responses have not been well studied. We are thus developing a mouse model of late-term maternal ZIKV infection in an immunocompetent, humanized mouse line. This work includes multi-omic analyses of brain development over the lifespan, as well as robust analysis of changes to host behavior in animals born to ZIKV-infected mothers.

Related projects seek to assess how the cell-intrinsic innate immune responses of neurons impact neural physiology, including neurotransmission. Intriguingly, our transcriptomic analysis of ZIKV-infected neurons has revealed that infection dysregulates many gene pathways related to basic neural function, including neurotransmitter biology, ion channel function, and neurite development. We thus aim to perform groundbreaking new work examining the direct impact of neuron-intrinsic immune signaling on fundamental aspects of neuronal cell biology, using imaging, electrophysiology, and pharmacogenetics. This exciting work stands to bridge the gap between basic immunology and basic neuroscience.

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We are developing a model of ZIKV infection during late gestation to assess the impact of maternal anti-ZIKV immunity on brain and behavioral development in offspring. This work is currently funded by NIH R21 MH125034.