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

Kim SB, Choi JY, Uyangaa E, Patil AM, Hossain FM, Hur J, Park SY, Lee JH, Kim K, Eo SK - J Neuroinflammation (2016)

Bottom Line: Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function.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-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells.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.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, 54596, Republic of Korea.

ABSTRACT

Background: Japanese 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.

Methods: Mice 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.

Results: Elevated 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-6C(hi) 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.

Conclusions: Inhibition 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.

No MeSH data available.


Related in: MedlinePlus

IDO ablation in HSC-derived leukocytes alleviates JE via enhancement of the IFN-I innate response. BM cells from WT or IDO KO mice were grafted to lethally irradiated WT or IDO KO recipient mice, which were then infected with JEV (3.0 × 107 PFU). a Susceptibility of IDO KO BM chimeric models to JE. Infected recipient mice (n = 12) were examined over 18 days to determine the survival rate. b Changes in body weight. Data are expressed as the average percentage of body weight relative to the time of challenge. c Systemic IFN-β levels in an IDO KO BM chimera. The amount of serum IFN-β was determined by ELISA at the indicated time points. *p < 0.05; **p < 0.01 compared with levels in WT-WT BM chimera 48 h pi. #p < 0.05; ##p < 0.01 compared with levels in WT-WT BM chimera 72 h pi
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Fig11: IDO ablation in HSC-derived leukocytes alleviates JE via enhancement of the IFN-I innate response. BM cells from WT or IDO KO mice were grafted to lethally irradiated WT or IDO KO recipient mice, which were then infected with JEV (3.0 × 107 PFU). a Susceptibility of IDO KO BM chimeric models to JE. Infected recipient mice (n = 12) were examined over 18 days to determine the survival rate. b Changes in body weight. Data are expressed as the average percentage of body weight relative to the time of challenge. c Systemic IFN-β levels in an IDO KO BM chimera. The amount of serum IFN-β was determined by ELISA at the indicated time points. *p < 0.05; **p < 0.01 compared with levels in WT-WT BM chimera 48 h pi. #p < 0.05; ##p < 0.01 compared with levels in WT-WT BM chimera 72 h pi

Mentions: Our results support the idea that IDO ablation ameliorates JE progression by provoking potent antiviral IFN-I innate responses in myeloid-derived DCs and pDCs at the periphery. Therefore, we were interested in confirming whether myeloid cells derived from hematopoietic stem cells (HSCs) play a dominant role in regulating JE progression in IDO-ablated mice via the induction of enhanced IFN-I innate responses. To this end, we used a BM chimeric model of wild-type BL/6 and IDO-ablated mice. In support of our hypothesis, our results revealed that myeloid cells derived from HSCs played a dominant role in conferring amelioration of JE in the IDO-ablated environment. Specifically, wild-type BL/6 recipients of IDO KO BM donor cells (KO-WT) showed enhanced resistance to JE, compared to the IDO KO recipients of wild-type BL/6 BM donor cells (WT-KO) and wild-type BL/6 recipients of wild-type BL/6 BM donor cells (WT-WT) (Fig. 11a). Furthermore, KO-WT and KO-KO BM chimeric models showed less change in body weight after JEV infection compared to the other BM chimeric models (Fig. 11b). Also, potent and rapid IFN-I innate immune responses were observed in KO-WT and KO-KO BM chimeric models compared to those observed in the WT-WT BM chimeric model, as evaluated by the determination of serum IFN-β (Fig. 11c). This result indicates that myeloid cells derived from HSCs of IDO-ablated mice play a dominant role in the IFN-I innate response in IDO KO hosts. Collectively, it appears that the ablation of IDO in myeloid cells derived from HSCs has an important role in ameliorating JE by inducing a potent and rapid IFN-I innate immune response.Fig. 11


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

Kim SB, Choi JY, Uyangaa E, Patil AM, Hossain FM, Hur J, Park SY, Lee JH, Kim K, Eo SK - J Neuroinflammation (2016)

IDO ablation in HSC-derived leukocytes alleviates JE via enhancement of the IFN-I innate response. BM cells from WT or IDO KO mice were grafted to lethally irradiated WT or IDO KO recipient mice, which were then infected with JEV (3.0 × 107 PFU). a Susceptibility of IDO KO BM chimeric models to JE. Infected recipient mice (n = 12) were examined over 18 days to determine the survival rate. b Changes in body weight. Data are expressed as the average percentage of body weight relative to the time of challenge. c Systemic IFN-β levels in an IDO KO BM chimera. The amount of serum IFN-β was determined by ELISA at the indicated time points. *p < 0.05; **p < 0.01 compared with levels in WT-WT BM chimera 48 h pi. #p < 0.05; ##p < 0.01 compared with levels in WT-WT BM chimera 72 h pi
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Fig11: IDO ablation in HSC-derived leukocytes alleviates JE via enhancement of the IFN-I innate response. BM cells from WT or IDO KO mice were grafted to lethally irradiated WT or IDO KO recipient mice, which were then infected with JEV (3.0 × 107 PFU). a Susceptibility of IDO KO BM chimeric models to JE. Infected recipient mice (n = 12) were examined over 18 days to determine the survival rate. b Changes in body weight. Data are expressed as the average percentage of body weight relative to the time of challenge. c Systemic IFN-β levels in an IDO KO BM chimera. The amount of serum IFN-β was determined by ELISA at the indicated time points. *p < 0.05; **p < 0.01 compared with levels in WT-WT BM chimera 48 h pi. #p < 0.05; ##p < 0.01 compared with levels in WT-WT BM chimera 72 h pi
Mentions: Our results support the idea that IDO ablation ameliorates JE progression by provoking potent antiviral IFN-I innate responses in myeloid-derived DCs and pDCs at the periphery. Therefore, we were interested in confirming whether myeloid cells derived from hematopoietic stem cells (HSCs) play a dominant role in regulating JE progression in IDO-ablated mice via the induction of enhanced IFN-I innate responses. To this end, we used a BM chimeric model of wild-type BL/6 and IDO-ablated mice. In support of our hypothesis, our results revealed that myeloid cells derived from HSCs played a dominant role in conferring amelioration of JE in the IDO-ablated environment. Specifically, wild-type BL/6 recipients of IDO KO BM donor cells (KO-WT) showed enhanced resistance to JE, compared to the IDO KO recipients of wild-type BL/6 BM donor cells (WT-KO) and wild-type BL/6 recipients of wild-type BL/6 BM donor cells (WT-WT) (Fig. 11a). Furthermore, KO-WT and KO-KO BM chimeric models showed less change in body weight after JEV infection compared to the other BM chimeric models (Fig. 11b). Also, potent and rapid IFN-I innate immune responses were observed in KO-WT and KO-KO BM chimeric models compared to those observed in the WT-WT BM chimeric model, as evaluated by the determination of serum IFN-β (Fig. 11c). This result indicates that myeloid cells derived from HSCs of IDO-ablated mice play a dominant role in the IFN-I innate response in IDO KO hosts. Collectively, it appears that the ablation of IDO in myeloid cells derived from HSCs has an important role in ameliorating JE by inducing a potent and rapid IFN-I innate immune response.Fig. 11

Bottom Line: Indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme associated with immunoregulatory function.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-6C(hi) monocytes, NK, CD4(+), and CD8(+) T-cells.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.

View Article: PubMed Central - PubMed

Affiliation: College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Iksan, 54596, Republic of Korea.

ABSTRACT

Background: Japanese 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.

Methods: Mice 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.

Results: Elevated 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-6C(hi) 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.

Conclusions: Inhibition 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.

No MeSH data available.


Related in: MedlinePlus