The brain parenchyma has a type I interferon response that can limit virus spread

Drokhlyansky, Eugene; Ayturk, Didem; Soh, Timothy K.; Chrenek, Ryan; O’Loughlin, Elaine; Madore, Charlotte; Butovsky, Oleg; Cepko, Constance L.

doi:10.1073/pnas.1618157114

Cited by 50 publications

(39 citation statements)

References 78 publications

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“…Surprisingly, genes for IFNα were not detected in any cells, despite the presence of pDCs that are typically the main source of type I interferons in the periphery (Fitzgerald-Bocarsly et al, 2008). These results are consistent with previous reports of IFNβ production from microglia to limit viral spread (Drokhlyansky et al, 2017). However, our results contrast with previous reports that identified astrocytes as the primary source of IFNβ (Pfefferkorn et al, 2016), which may be due to differences in the methods used to identify IFNβ-producing cells.…”

Section: Type I Interferon Responses Are Mediated By the Release Of Isupporting

confidence: 81%

Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses

Huang

Sabatini

2020

Front. Cell. Neurosci.

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Viral vectors are essential tools for the study of neural circuits, with glycoprotein-deleted rabies viruses being widely used for monosynaptic retrograde tracing to map connectivity between specific cell types in the nervous system. However, the use of rabies virus is limited by the cytotoxicity and the inflammatory responses these viruses trigger. While components of the rabies virus genome contribute to its cytotoxic effects, the function of other neuronal and non-neuronal cells within the vicinity of the infected host neurons in either effecting or mitigating virally-induced tissue damage are still being elucidated. Here, we analyzed 60,212 single-cell RNA profiles to assess both global and cell-typespecific transcriptional responses in the mouse dorsal raphe nucleus (DRN) following intracranial injection of glycoprotein-deleted rabies viruses and axonal infection of dorsal raphe serotonergic neurons. Gene pathway analyses revealed a down-regulation of genes involved in metabolic processes and neurotransmission following infection. We also identified several transcriptionally diverse leukocyte populations that infiltrate the brain and are distinct from resident immune cells. Cell type-specific patterns of cytokine expression showed that antiviral responses were likely orchestrated by Type I and Type II interferon signaling from microglia and infiltrating CD4 + T cells, respectively. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, which range from surveillance to antigen presentation and cytokine secretion. Intercellular interactions inferred from transcriptional data suggest that CD4 + T cells facilitate microglial state transitions during the inflammatory response. Our study uncovers the heterogeneity of immune cells mediating neuroinflammatory responses and provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in mediating different facets of antiviral responses in the brain and will facilitate the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery.

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Section: Type I Interferon Responses Are Mediated By the Release Of Isupporting

confidence: 81%

Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses

Huang

Sabatini

2020

Front. Cell. Neurosci.

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“…Surprisingly, genes for IFNα were not detected in any cells, despite the presence of pDCs that are typically the main source of type I interferons in the periphery 34 . These results are consistent with previous reports of IFNβ production from microglia to limit viral spread 35 . However, our results contrast with previous reports that identified astrocytes as the primary source of IFNβ 36 , which may be due to differences in the methods used to identify IFNβ-producing cells.…”

Section: Type I Interferon Responses Are Mediated By Release Of Ifnβ supporting

confidence: 94%

Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus

Huang

Sabatini

2019

Preprint

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Neuroinflammatory processes have been implicated in neurodegenerative and psychiatric diseases, and limit the utility of viruses for gene delivery. Here we analyzed 60,212 single-cell RNA profiles to assess both global and cell type-specific transcriptional responses in the mouse dorsal raphe nucleus following axonal infection of neurons by rabies viruses. We identified several leukocyte populations, which infiltrate the brain, that are distinct from resident immune cells. Additionally, we uncovered transcriptionally distinct states of microglia along an activation trajectory that may serve different functions, ranging from surveillance to antigen presentation and cytokine secretion. Our study also provides a critical evaluation of the compatibility between rabies-mediated connectivity mapping and single-cell transcriptional profiling. These findings provide additional insights into the distinct contributions of various cell types in the antiviral response, and will serve as a resource for the design of strategies to circumvent immune responses to improve the efficacy of viral gene delivery.

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“…For brain collection, the brain was removed, quartered and frozen in a 1.5 mL tube on dry ice. Frozen tissue was stored at −80°C until subsequent tissue processing.Tissue collection and preparation for RNA fluorescence in situ hybridization and immunohistochemistryFor RNA fluorescence in situ hybridization (RNA FISH) and Immunohistochemistry (IHC), isolated colon was cut into four sections of equal size and processed as described(140). Briefly, tissue was fixed in 4% paraformaldehyde overnight at 4°C.…”

mentioning

confidence: 99%

The enteric nervous system of the human and mouse colon at a single-cell resolution

Drokhlyansky

Smillie

Wittenberghe

et al. 2019

Preprint

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As the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.

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The brain parenchyma has a type I interferon response that can limit virus spread

Cited by 50 publications

References 78 publications

Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses

Single-Cell Analysis of Neuroinflammatory Responses Following Intracranial Injection of G-Deleted Rabies Viruses

Single-cell analysis of antiviral neuroinflammatory responses in the mouse dorsal raphe nucleus

The enteric nervous system of the human and mouse colon at a single-cell resolution

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