Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response
Abstract Background Zika virus (ZIKV) infection at postnatal or adult age can lead to neurological disorders associated with cognitive defects. Yet, how mature neurons respond to ZIKV remains substantially unexplored. Methods The impact of ZIKV infection on mature neurons and microglia was analyzed...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02668-8 |
| _version_ | 1797977346304638976 |
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| author | Caroline Manet Zeyni Mansuroglu Laurine Conquet Violaine Bortolin Thomas Comptdaer Helena Segrt Marie Bourdon Reyene Menidjel Nicolas Stadler Guanfang Tian Floriane Herit Florence Niedergang Sylvie Souès Luc Buée Marie-Christine Galas Xavier Montagutelli Eliette Bonnefoy |
| author_facet | Caroline Manet Zeyni Mansuroglu Laurine Conquet Violaine Bortolin Thomas Comptdaer Helena Segrt Marie Bourdon Reyene Menidjel Nicolas Stadler Guanfang Tian Floriane Herit Florence Niedergang Sylvie Souès Luc Buée Marie-Christine Galas Xavier Montagutelli Eliette Bonnefoy |
| author_sort | Caroline Manet |
| collection | DOAJ |
| description | Abstract Background Zika virus (ZIKV) infection at postnatal or adult age can lead to neurological disorders associated with cognitive defects. Yet, how mature neurons respond to ZIKV remains substantially unexplored. Methods The impact of ZIKV infection on mature neurons and microglia was analyzed at the molecular and cellular levels, in vitro using immunocompetent primary cultured neurons and microglia, and in vivo in the brain of adult immunocompetent mice following intracranial ZIKV inoculation. We have used C57BL/6 and the genetically diverse Collaborative Cross mouse strains, displaying a broad range of susceptibility to ZIKV infection, to question the correlation between the effects induced by ZIKV infection on neurons and microglia and the in vivo susceptibility to ZIKV. Results As a result of a delayed induction of interferon beta (IFNB) expression and response, infected neurons displayed an inability to stop ZIKV replication, a trait that was further increased in neurons from susceptible mice. Alongside with an enhanced expression of ZIKV RNA, we observed in vivo, in the brain of susceptible mice, an increased level of active Iba1-expressing microglial cells occasionally engulfing neurons and displaying a gene expression profile close to the molecular signature of disease-associated microglia (DAM). In vivo as well as in vitro, only neurons and not microglial cells were identified as infected, raising the question of the mechanisms underlying microglia activation following brain ZIKV infection. Treatment of primary cultured microglia with conditioned media from ZIKV-infected neurons demonstrated that type-I interferons (IFNs-I) secreted by neurons late after infection activate non-infected microglial cells. In addition, ZIKV infection induced pathological phosphorylation of Tau (pTau) protein, a hallmark of neurodegenerative tauopathies, in vitro and in vivo with clusters of neurons displaying pTau surrounded by active microglial cells. Conclusions We show that ZIKV-infected mature neurons display an inability to stop viral replication in link with a delayed IFNB expression and response, while signaling microglia for activation through IFNs-I secreted at late times post-infection. In the brain of ZIKV-infected susceptible mice, uninfected microglial cells adopt an active morphology and a DAM expression profile, surrounding and sometimes engulfing neurons while ZIKV-infected neurons accumulate pTau, overall reflecting a tauopathy-like phenotype. |
| first_indexed | 2024-04-11T05:05:20Z |
| format | Article |
| id | doaj.art-81dd2648612b489ba907fdab7786cc88 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T05:05:20Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-81dd2648612b489ba907fdab7786cc882022-12-25T12:23:53ZengBMCJournal of Neuroinflammation1742-20942022-12-0119112110.1186/s12974-022-02668-8Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta responseCaroline Manet0Zeyni Mansuroglu1Laurine Conquet2Violaine Bortolin3Thomas Comptdaer4Helena Segrt5Marie Bourdon6Reyene Menidjel7Nicolas Stadler8Guanfang Tian9Floriane Herit10Florence Niedergang11Sylvie Souès12Luc Buée13Marie-Christine Galas14Xavier Montagutelli15Eliette Bonnefoy16Institut Pasteur, Mouse Genetics Laboratory, Université de ParisUniversité Paris Cité, Institut Cochin, Inserm, CNRSInstitut Pasteur, Mouse Genetics Laboratory, Université de ParisUniversité Paris Cité, Institut Cochin, Inserm, CNRSUniversity Lille, Inserm, CHU Lille, Inserm, LilNCog - Lille Neuroscience & CognitionUniversité Paris Cité, Institut Cochin, Inserm, CNRSInstitut Pasteur, Mouse Genetics Laboratory, Université de ParisUniversité Paris Cité, Institut Cochin, Inserm, CNRSUniversité Paris Cité, Inserm UMR1124Université Paris Cité, Institut Cochin, Inserm, CNRSUniversité Paris Cité, Institut Cochin, Inserm, CNRSUniversité Paris Cité, Institut Cochin, Inserm, CNRSUniversité Paris Cité, Institut Cochin, Inserm, CNRSUniversity Lille, Inserm, CHU Lille, Inserm, LilNCog - Lille Neuroscience & CognitionUniversity Lille, Inserm, CHU Lille, Inserm, LilNCog - Lille Neuroscience & CognitionInstitut Pasteur, Mouse Genetics Laboratory, Université de ParisUniversité Paris Cité, Institut Cochin, Inserm, CNRSAbstract Background Zika virus (ZIKV) infection at postnatal or adult age can lead to neurological disorders associated with cognitive defects. Yet, how mature neurons respond to ZIKV remains substantially unexplored. Methods The impact of ZIKV infection on mature neurons and microglia was analyzed at the molecular and cellular levels, in vitro using immunocompetent primary cultured neurons and microglia, and in vivo in the brain of adult immunocompetent mice following intracranial ZIKV inoculation. We have used C57BL/6 and the genetically diverse Collaborative Cross mouse strains, displaying a broad range of susceptibility to ZIKV infection, to question the correlation between the effects induced by ZIKV infection on neurons and microglia and the in vivo susceptibility to ZIKV. Results As a result of a delayed induction of interferon beta (IFNB) expression and response, infected neurons displayed an inability to stop ZIKV replication, a trait that was further increased in neurons from susceptible mice. Alongside with an enhanced expression of ZIKV RNA, we observed in vivo, in the brain of susceptible mice, an increased level of active Iba1-expressing microglial cells occasionally engulfing neurons and displaying a gene expression profile close to the molecular signature of disease-associated microglia (DAM). In vivo as well as in vitro, only neurons and not microglial cells were identified as infected, raising the question of the mechanisms underlying microglia activation following brain ZIKV infection. Treatment of primary cultured microglia with conditioned media from ZIKV-infected neurons demonstrated that type-I interferons (IFNs-I) secreted by neurons late after infection activate non-infected microglial cells. In addition, ZIKV infection induced pathological phosphorylation of Tau (pTau) protein, a hallmark of neurodegenerative tauopathies, in vitro and in vivo with clusters of neurons displaying pTau surrounded by active microglial cells. Conclusions We show that ZIKV-infected mature neurons display an inability to stop viral replication in link with a delayed IFNB expression and response, while signaling microglia for activation through IFNs-I secreted at late times post-infection. In the brain of ZIKV-infected susceptible mice, uninfected microglial cells adopt an active morphology and a DAM expression profile, surrounding and sometimes engulfing neurons while ZIKV-infected neurons accumulate pTau, overall reflecting a tauopathy-like phenotype.https://doi.org/10.1186/s12974-022-02668-8Zika virusInterferon betaTau proteinCollaborative crossDisease associated microgliaNeuron-microglia crosstalk |
| spellingShingle | Caroline Manet Zeyni Mansuroglu Laurine Conquet Violaine Bortolin Thomas Comptdaer Helena Segrt Marie Bourdon Reyene Menidjel Nicolas Stadler Guanfang Tian Floriane Herit Florence Niedergang Sylvie Souès Luc Buée Marie-Christine Galas Xavier Montagutelli Eliette Bonnefoy Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response Journal of Neuroinflammation Zika virus Interferon beta Tau protein Collaborative cross Disease associated microglia Neuron-microglia crosstalk |
| title | Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response |
| title_full | Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response |
| title_fullStr | Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response |
| title_full_unstemmed | Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response |
| title_short | Zika virus infection of mature neurons from immunocompetent mice generates a disease-associated microglia and a tauopathy-like phenotype in link with a delayed interferon beta response |
| title_sort | zika virus infection of mature neurons from immunocompetent mice generates a disease associated microglia and a tauopathy like phenotype in link with a delayed interferon beta response |
| topic | Zika virus Interferon beta Tau protein Collaborative cross Disease associated microglia Neuron-microglia crosstalk |
| url | https://doi.org/10.1186/s12974-022-02668-8 |
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