RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection.
Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-11-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011813&type=printable |
| _version_ | 1797377773290913792 |
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| author | Marissa Lindman Juan P Angel Irving Estevez Nydia P Chang Tsui-Wen Chou Micheal McCourt Colm Atkins Brian P Daniels |
| author_facet | Marissa Lindman Juan P Angel Irving Estevez Nydia P Chang Tsui-Wen Chou Micheal McCourt Colm Atkins Brian P Daniels |
| author_sort | Marissa Lindman |
| collection | DOAJ |
| description | Innate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3-mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS. |
| first_indexed | 2024-03-08T19:58:20Z |
| format | Article |
| id | doaj.art-95b0876651d4404cae13fd2171846993 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-03-08T19:58:20Z |
| publishDate | 2023-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-95b0876651d4404cae13fd21718469932023-12-24T05:31:57ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-11-011911e101181310.1371/journal.ppat.1011813RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection.Marissa LindmanJuan P AngelIrving EstevezNydia P ChangTsui-Wen ChouMicheal McCourtColm AtkinsBrian P DanielsInnate immune signaling in the central nervous system (CNS) exhibits many remarkable specializations that vary across cell types and CNS regions. In the setting of neuroinvasive flavivirus infection, neurons employ the immunologic kinase receptor-interacting kinase 3 (RIPK3) to promote an antiviral transcriptional program, independently of the traditional function of this enzyme in promoting necroptotic cell death. However, while recent work has established roles for neuronal RIPK3 signaling in controlling mosquito-borne flavivirus infections, including West Nile virus and Zika virus, functions for RIPK3 signaling in the CNS during tick-borne flavivirus infection have not yet been explored. Here, we use a model of Langat virus (LGTV) encephalitis to show that RIPK3 signaling is specifically required in neurons of the cerebellum to control LGTV replication and restrict disease pathogenesis. This effect did not require the necroptotic executioner molecule mixed lineage kinase domain like protein (MLKL), a finding similar to previous observations in models of mosquito-borne flavivirus infection. However, control of LGTV infection required a unique, region-specific dependence on RIPK3 to promote expression of key antiviral interferon-stimulated genes (ISG) in the cerebellum. This RIPK3-mediated potentiation of ISG expression was associated with robust cell-intrinsic restriction of LGTV replication in cerebellar granule cell neurons. These findings further illuminate the complex roles of RIPK3 signaling in the coordination of neuroimmune responses to viral infection, as well as provide new insight into the mechanisms of region-specific innate immune signaling in the CNS.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011813&type=printable |
| spellingShingle | Marissa Lindman Juan P Angel Irving Estevez Nydia P Chang Tsui-Wen Chou Micheal McCourt Colm Atkins Brian P Daniels RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. PLoS Pathogens |
| title | RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. |
| title_full | RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. |
| title_fullStr | RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. |
| title_full_unstemmed | RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. |
| title_short | RIPK3 promotes brain region-specific interferon signaling and restriction of tick-borne flavivirus infection. |
| title_sort | ripk3 promotes brain region specific interferon signaling and restriction of tick borne flavivirus infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1011813&type=printable |
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