Modulation of systemic and mucosal immunity against an inactivated vaccine of Newcastle disease virus by oral co-administration of live attenuated <i>Salmonella enterica</i> serovar Typhimurium expressing chicken interleukin-18 and interferon-α

RAHMAN, Md. Masudur,UYANGAA, Erdenebelig,HAN, Young Woo,HUR, Jin,PARK, Sang-Youel,LEE, John Hwa,KIM, Koanhoi,EO, Seong Kug The Japanese Society of Veterinary Science 2015 The Journal of veterinary medical science Vol.77 No.4

<P>Newcastle disease (ND) is a highly contagious disease of chickens causing significant economic losses worldwide. Due to limitations in the efficacy against currently circulating ND viruses, existing vaccination strategies require improvements, and incorporating immunomodulatory cytokines with existing vaccines might be a novel approach. Here, we investigated the systemic and mucosal immunomodulatory properties of oral co-administration of chicken interleukin-18 (chIL-18) and chicken interferon-α (chIFN-α) using attenuated <I>Salmonella enterica</I> serovar Typhimurium on an inactivated ND vaccine. Our results demonstrate that oral administration of <I>S. enterica</I> serovar Typhimurium expressing chIL-18 or chIFN-α provided enhanced systemic and mucosal immune responses, as determined by serum hemagglutination inhibition antibody and NDV Ag-specific IgG as well as NDV Ag-specific IgA in lung and duodenal lavages of chickens immunized with inactivated ND vaccine via the intramuscular or intranasal route. Notably, combined oral administration of <I>S. enterica</I> serovar Typhimurium expressing chIL-18 and chIFN-α significantly enhanced systemic and mucosal immunity in ND-vaccinated chickens, compared to single administration of <I>S. enterica</I> serovar Typhimurium expressing chIL-18 or chIFN-α. In addition, oral co-administration of <I>S. enterica</I> serovar Typhimurium expressing chIL-18 and chIFN-α provided enhanced NDV Ag-specific proliferation of peripheral blood mononuclear cells and Th1-biased cell-mediated immunity, compared to single administration of either construct. Therefore, our results provide valuable insight into the modulation of systemic and mucosal immunity by incorporation of immunomodulatory chIL-18 and chIFN-α using <I>Salmonella</I> vaccines into existing ND vaccines.</P>

Distinct Dictation of Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality via Triggering TLR3 and TLR4 Signal Pathways

Han, Young Woo,Choi, Jin Young,Uyangaa, Erdenebelig,Kim, Seong Bum,Kim, Jin Hyoung,Kim, Bum Seok,Kim, Koanhoi,Eo, Seong Kug Public Library of Science 2014 PLoS pathogens Vol.10 No.9

<▼1><P>Japanese encephalitis (JE) is major emerging neurologic disease caused by JE virus. To date, the impact of TLR molecules on JE progression has not been addressed. Here, we determined whether each TLR modulates JE, using several TLR-deficient mouse strains (TLR2, TLR3, TLR4, TLR7, TLR9). Surprisingly, among the tested TLR-deficient mice there were contrasting results in TLR3<SUP>−/−</SUP> and TLR4<SUP>−/−</SUP> mice, <I>i.e.</I> TLR3<SUP>−/−</SUP> mice were highly susceptible to JE, whereas TLR4<SUP>−/−</SUP> mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation characterized by early infiltration of inflammatory CD11b<SUP>+</SUP>Ly-6C<SUP>high</SUP> monocytes along with profoundly increased viral burden, proinflammatory cytokine/chemokine expression as well as BBB permeability. In contrast, TLR4<SUP>−/−</SUP> mice showed mild CNS inflammation manifested by reduced viral burden, leukocyte infiltration and proinflammatory cytokine expression. Interestingly, TLR4 ablation provided potent <I>in vivo</I> systemic type I IFN innate response, as well as <I>ex vivo</I> type I IFN production associated with strong induction of antiviral PRRs (RIG-I, MDA5), transcription factors (IRF-3, IRF-7), and IFN-dependent (PKR, Oas1, Mx) and independent ISGs (ISG49, ISG54, ISG56) by alternative activation of IRF3 and NF-κB in myeloid-derived DCs and macrophages, as compared to TLR3<SUP>−/−</SUP> myeloid-derived cells which were more permissive to viral replication through impaired type I IFN innate response. TLR4 ablation also appeared to mount an enhanced type I IFN innate and humoral, CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T cell responses, which were mediated by altered immune cell populations (increased number of plasmacytoid DCs and NK cells, reduced CD11b<SUP>+</SUP>Ly-6C<SUP>high</SUP> monocytes) and CD4<SUP>+</SUP>Foxp3<SUP>+</SUP> Treg number in lymphoid tissue. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were closely coupled with reduced JE lethality. Collectively, these results suggest that a balanced triggering of TLR signal array by viral components during JE progression could be responsible for determining disease outcome through regulating negative and positive factors.</P></▼1><▼2><P><B>Author Summary</B></P><P>Japanese encephalitis (JE) is major emerging encephalitis, and more than 60% of global population inhabits JE endemic areas. The etiological virus is currently spreading to previously unaffected regions due to rapid changes in climate and demography. However, the impact of TLR molecules on JE progression has not been addressed to date. We found that the distinct outcomes of JE progression occurred in TLR3 and TLR4-dependent manner, <I>i.e.</I> TLR3<SUP>−/−</SUP> mice were highly susceptible, whereas TLR4<SUP>−/−</SUP> mice showed enhanced resistance to JE. TLR3 ablation induced severe CNS inflammation manifested by early CD11b<SUP>+</SUP>Ly-6C<SUP>high</SUP> monocyte infiltration, high expression of proinflammatory cytokines, as well as increased BBB permeability. In contrast, TLR4 ablation provided potent type I IFN innate response in infected mice, as well as in myeloid-derived cells closely associated with strong induction of antiviral ISG genes, and also resulted in enhanced humoral, CD4+, and CD8+ T cell responses along with altered plasmacytoid DC and CD4<SUP>+</SUP>Foxp3<SUP>+</SUP> Treg number. Thus, potent type I IFN innate and adaptive immune responses in the absence of TLR4 were coupled with reduced JE lethality. Our studies provide an insight into the role of each TLR molecule on the modulation of JE, as well as its mechanism of neuroinflammation control during JE progression.</P></▼2>

Exacerbation of Japanese Encephalitis by CD11c<SUP>hi</SUP> Dendritic Cell Ablation Is Associated with an Imbalance in Regulatory Foxp3<SUP>+</SUP> and IL-17<SUP>+</SUP>CD4<SUP>+</SUP> Th17 Cells and in Ly-6C<SUP>hi</SUP> and Ly-6C<SUP>lo</SUP> Monocytes

Jin Young Choi,Jin Hyoung Kim,Ajit Mahadev Patil,Seong Bum Kim,Erdenebelig Uyangaa,Ferdaus Mohd Altaf Hossain,Seong Kug Eo 대한면역학회 2017 Immune Network Vol.17 No.3

Indoleamine 2,3-Dioxygenase in Hematopoietic Stem Cell-Derived Cells Suppresses Rhinovirus-Induced Neutrophilic Airway Inflammation by Regulating Th1- and Th17-Type Responses

Hossain Ferdaus Mohd Altaf,박성옥,김효진,어준철,최진영,Tanveer Maryum,Uyangaa Erdenebelig,김관회,어성국 대한면역학회 2021 Immune Network Vol.21 No.4

Asthma exacerbations are a major cause of intractable morbidity, increases in health care costs, and a greater progressive loss of lung function. Asthma exacerbations are most commonly triggered by respiratory viral infections, particularly with human rhinovirus (hRV). Respiratory viral infections are believed to affect the expression of indoleamine 2,3-dioxygenase (IDO), a limiting enzyme in tryptophan catabolism, which is presumed to alter asthmatic airway inflammation. Here, we explored the detailed role of IDO in the progression of asthma exacerbations using a mouse model for asthma exacerbation caused by hRV infection. Our results reveal that IDO is required to prevent neutrophilic inflammation in the course of asthma exacerbation caused by an hRV infection, as corroborated by markedly enhanced Th17- and Th1-type neutrophilia in the airways of IDO-deficient mice. This neutrophilia was closely associated with disrupted expression of tight junctions and enhanced expression of inflammasome-related molecules and mucin-inducing genes. In addition, IDO ablation enhanced allergen-specific Th17- and Th1-biased CD4+ T-cell responses following hRV infection. The role of IDO in attenuating Th17- and Th1-type neutrophilic airway inflammation became more apparent in chronic asthma exacerbations after repeated allergen exposures and hRV infections. Furthermore, IDO enzymatic induction in leukocytes derived from the hematopoietic stem cell (HSC) lineage appeared to play a dominant role in attenuating Th17- and Th1-type neutrophilic inflammation in the airway following hRV infection. Therefore, IDO activity in HSC-derived leukocytes is required to regulate Th17- and Th1-type neutrophilic inflammation in the airway during asthma exacerbations caused by hRV infections.