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

Abstract

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.

Fundamental neurochemistry review: Glutamatergic dysfunction as a central mechanism underlying flavivirus‐induced neurological damage

“…Other players of the kynurenine pathway were also altered by ZIKV in HepG2 cells (Giovannoni et al, 2020). In addition, genetic knockout of IDO-1 caused partial reversion of ZIKV-induced gliosis and cell death (Marim et al, 2021).…”

“…ZIKV was shown to increase the expression of indoleamine‐2,3‐dioxygenase (IDO‐1) in HepG2 cells, primary cultures of murine cortical‐striatal neurons and in AG129 mice (Giovannoni et al, 2020; Marim et al, 2021). IDO‐1 is the limiting enzyme of the kynurenine pathway, responsible for suppression of both innate and adaptative immunity (Mithaiwala et al, 2021).…”

“…Other players of the kynurenine pathway were also altered by ZIKV in HepG2 cells (Giovannoni et al, 2020). In addition, genetic knockout of IDO‐1 caused partial reversion of ZIKV‐induced gliosis and cell death (Marim et al, 2021). Two main metabolites of the pathway are implicated in NMDAR modulation, namely quinolinic acid, with agonist properties, and kynurenic acid, with antagonist properties.…”

The Potential Neuroprotective Effect of Cyperus esculentus L. Extract in Scopolamine-Induced Cognitive Impairment in Rats: Extensive Biological and Metabolomics Approaches

“…or organic acids (quinic acid and citric acid, etc.). Some of these have also been shown to play a role in neurodegenerative processes, such as tryptophan-related metabolites [ 30 ]. However, the relative abundance of these metabolites seems minor compared with the fatty acids detected.…”

Innate antiviral immunity: how prior exposures can guide future responses

“…Moreover, tryptophan metabolites have been ascribed a putative neuroprotective role and might suppress inflammation in the central nervous system (CNS) during multiple sclerosis in vivo in mouse models and in humans, although this warrants further investigation [43,44]. Nevertheless, aligned with this concept, inhibition of tryptophan metabolite signaling in mice has led to reduced neuronal death following Zika virus infection [45]. Of note, the tryptophan metabolite 5-hydroxytrytophan has been reported to be required for parainfluenza viral replication in vitro in human A549 lung cells [46], suggesting that tryptophan and/or its related metabolites might functionally alter antiviral signaling and/or directly promote viral replication, although this will require further rigorous testing.…”