Blockage of indoleamine 2,3-dioxygenase regulates Japanese encephalitis via enhancement of type I/II IFN innate and adaptive T-cell responses

Abstract

BackgroundJapanese encephalitis (JE), a leading cause of viral encephalitis, is characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV). Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function. Although the regulatory role of IDO in viral replication has been postulated, the in vivo role of IDO activity has not been fully addressed in neurotropic virus-caused encephalitis.MethodsMice in which IDO activity was inhibited by genetic ablation or using a specific inhibitor were examined for mortality and clinical signs after infection. Neuroinflammation was evaluated by central nervous system (CNS) infiltration of leukocytes and cytokine expression. IDO expression, viral burden, JEV-specific T-cell, and type I/II interferon (IFN-I/II) innate responses were also analyzed.ResultsElevated expression of IDO activity in myeloid and neuron cells of the lymphoid and CNS tissues was closely associated with clinical signs of JE. Furthermore, inhibition of IDO activity enhanced resistance to JE, reduced the viral burden in lymphoid and CNS tissues, and resulted in early and increased CNS infiltration by Ly-6Chi monocytes, NK, CD4+, and CD8+ T-cells. JE amelioration in IDO-ablated mice was also associated with enhanced NK and JEV-specific T-cell responses. More interestingly, IDO ablation induced rapid enhancement of type I IFN (IFN-I) innate responses in CD11c+ dendritic cells (DCs), including conventional and plasmacytoid DCs, following JEV infection. This enhanced IFN-I innate response in IDO-ablated CD11c+ DCs was coupled with strong induction of PRRs (RIG-I, MDA5), transcription factors (IRF7, STAT1), and antiviral ISG genes (Mx1, Mx2, ISG49, ISG54, ISG56). IDO ablation also enhanced the IFN-I innate response in neuron cells, which may delay the spread of virus in the CNS. Finally, we identified that IDO ablation in myeloid cells derived from hematopoietic stem cells (HSCs) dominantly contributed to JE amelioration and that HSC-derived leukocytes played a key role in the enhanced IFN-I innate responses in the IDO-ablated environment.ConclusionsInhibition of IDO activity ameliorated JE via enhancement of antiviral IFN-I/II innate and adaptive T-cell responses and increased CNS infiltration of peripheral leukocytes. Therefore, our data provide valuable insight into the use of IDO inhibition by specific inhibitors as a promising tool for therapeutic and prophylactic strategies against viral encephalitis caused by neurotropic viruses.

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

“…33 Moreover, peripheral infection with Japanese encephalitis virus (JEV) increased Ido1 expression in the periphery and brain, and Ido1-KO mice were more resistant to encephalitis. 11 Although the authors from the latter study mentioned the occurrence of seizures caused by JEV, the effect of Ido1 on the incidence and/or severity of these seizures was not reported. Therefore, it remains to be determined whether Ido1 protection against viral encephalitic pathogenesis is specific for members of Picornaviridae.…”

“…For instance, intraperitoneal injection with encephalomyocarditis virus increased Ido1 expression in the cerebellum, where it colocalized to areas of reactive gliosis . Moreover, peripheral infection with Japanese encephalitis virus (JEV) increased Ido1 expression in the periphery and brain, and Ido1‐KO mice were more resistant to encephalitis . Although the authors from the latter study mentioned the occurrence of seizures caused by JEV, the effect of Ido1 on the incidence and/or severity of these seizures was not reported.…”

“…Although basal levels of Ido1 vary between tissue location and cell type, the expression of this enzyme is highly inducible by inflammatory mediators, in particular type II (IFN‐γ) IFNs. 11 Ido1 induction may lead to focal depletion of Trp at the site of inflammation or infection, which can directly limit viral replication . The intracellular Kyn generated by Ido1 is either released or metabolized into downstream “kynurenines” (kynurenic acid [KynA] or quinolinic acid [QuinA]), which have both neuro‐ and immunomodulatory consequences .…”

“…11 Ido1 induction may lead to focal depletion of Trp at the site of inflammation or infection, which can directly limit viral replication. 11 The intracellular Kyn generated by Ido1 is either released or metabolized into downstream "kynurenines" (kynurenic acid [KynA] or quinolinic acid [QuinA]), which have both neuro-and immunomodulatory consequences. 12,13 Extracellular KynA serves as an N-methyl-Daspartate (NMDA) receptor antagonist and is considered neuroprotective.…”

Viruses in human central nervous system — invasion, transmission, and latency: a literature review

“…Предполагают, что важную роль в этой регуляции играет высокая степень поляризации нейронов, обес-печивающая эффективную коммуникацию между не-рвным окончанием и телом клетки. Продуцирующиеся после проникновения вируса в клетки периферичес-кой ткани интерлейкины, фактор некроза опухоли, интерфероны оказывают влияние на все близлежа-щие аксоны [67,68]. Вследствие паракринного воз-действия цитокинов и эффективной коммуникации в нейронах уменьшается синтез мРНК, что препятствует транскрипции вирусного генома, и активизируется проапоптотический ген р53 [69].…”