Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection

Frontiers in Immunology

Danielle Cunha Teixeira¹  Fernanda Martins Marim¹  Bruno Vinicius Santos Valiate¹  Mauro Martins Teixeira¹  Jose Carlos Alves-Filho²  Thiago Mattar Cunha²  Celso Martins Queiroz-Junior³  Vivian Vasconcelos Costa³  Antonio Lucio Teixeira⁵  Robert Dantzer⁶ 

[1] Center for Drug Research and Development of Pharmaceuticals, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirao Preto Medical School, Universidade de São Paulo, Ribeirão Preto, Brazil;Departament of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;Department of Psychiatry and Behavioral Sciences, McGovern Medical Houston, The University of Texas Health Science Center at Houston, Houston, TX, United States;Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Research Group in Arboviral Diseases, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;

关键词: Zika virus;    IDO-1;    neuroinflammation;    neuronal death;    microgliosis;   

DOI  :  10.3389/fimmu.2021.702048

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown