Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection
Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.702048/full |
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| author | Fernanda Martins Marim Fernanda Martins Marim Fernanda Martins Marim Danielle Cunha Teixeira Danielle Cunha Teixeira Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Bruno Vinicius Santos Valiate Bruno Vinicius Santos Valiate Jose Carlos Alves-Filho Thiago Mattar Cunha Robert Dantzer Mauro Martins Teixeira Mauro Martins Teixeira Mauro Martins Teixeira Antonio Lucio Teixeira Vivian Vasconcelos Costa Vivian Vasconcelos Costa Vivian Vasconcelos Costa |
| author_facet | Fernanda Martins Marim Fernanda Martins Marim Fernanda Martins Marim Danielle Cunha Teixeira Danielle Cunha Teixeira Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Bruno Vinicius Santos Valiate Bruno Vinicius Santos Valiate Jose Carlos Alves-Filho Thiago Mattar Cunha Robert Dantzer Mauro Martins Teixeira Mauro Martins Teixeira Mauro Martins Teixeira Antonio Lucio Teixeira Vivian Vasconcelos Costa Vivian Vasconcelos Costa Vivian Vasconcelos Costa |
| author_sort | Fernanda Martins Marim |
| collection | DOAJ |
| description | Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment. |
| first_indexed | 2024-12-20T01:55:22Z |
| format | Article |
| id | doaj.art-d7b0316b46c74babaf141c95ccf3802f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T01:55:22Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d7b0316b46c74babaf141c95ccf3802f2022-12-21T19:57:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-07-011210.3389/fimmu.2021.702048702048Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus InfectionFernanda Martins Marim0Fernanda Martins Marim1Fernanda Martins Marim2Danielle Cunha Teixeira3Danielle Cunha Teixeira4Celso Martins Queiroz-Junior5Celso Martins Queiroz-Junior6Celso Martins Queiroz-Junior7Bruno Vinicius Santos Valiate8Bruno Vinicius Santos Valiate9Jose Carlos Alves-Filho10Thiago Mattar Cunha11Robert Dantzer12Mauro Martins Teixeira13Mauro Martins Teixeira14Mauro Martins Teixeira15Antonio Lucio Teixeira16Vivian Vasconcelos Costa17Vivian Vasconcelos Costa18Vivian Vasconcelos Costa19Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilResearch Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilResearch Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilResearch Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilDepartament of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilDepartment of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, Universidade de São Paulo, Ribeirão Preto, BrazilCenter for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, Universidade de São Paulo, Ribeirão Preto, BrazilDepartment of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilResearch Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilDepartment of Psychiatry and Behavioral Sciences, McGovern Medical Houston, The University of Texas Health Science Center at Houston, Houston, TX, United StatesResearch Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilCenter for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilDepartament of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, BrazilZika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment.https://www.frontiersin.org/articles/10.3389/fimmu.2021.702048/fullZika virusIDO-1neuroinflammationneuronal deathmicrogliosis |
| spellingShingle | Fernanda Martins Marim Fernanda Martins Marim Fernanda Martins Marim Danielle Cunha Teixeira Danielle Cunha Teixeira Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Celso Martins Queiroz-Junior Bruno Vinicius Santos Valiate Bruno Vinicius Santos Valiate Jose Carlos Alves-Filho Thiago Mattar Cunha Robert Dantzer Mauro Martins Teixeira Mauro Martins Teixeira Mauro Martins Teixeira Antonio Lucio Teixeira Vivian Vasconcelos Costa Vivian Vasconcelos Costa Vivian Vasconcelos Costa Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection Frontiers in Immunology Zika virus IDO-1 neuroinflammation neuronal death microgliosis |
| title | Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection |
| title_full | Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection |
| title_fullStr | Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection |
| title_full_unstemmed | Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection |
| title_short | Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection |
| title_sort | inhibition of tryptophan catabolism is associated with neuroprotection during zika virus infection |
| topic | Zika virus IDO-1 neuroinflammation neuronal death microgliosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.702048/full |
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