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      바이러스성 뇌염에서의 Toll-like receptor 와 CD4+CD25+Foxp3+ 조절 T 세포의 역할 연구

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      https://www.riss.kr/link?id=T12786352

      • 저자
      • 발행사항

        전주: 전북대학교 대학원, 2012

      • 학위논문사항

        학위논문(박사) -- 전북대학교 대학원 , 수의학 , 2012. 2

      • 발행연도

        2012

      • 작성언어

        영어

      • 발행국(도시)

        전북특별자치도

      • 기타서명

        The role of Toll-like receptors and CD4+CD25+Foxp3+ regulatory T cells in viral encephalitis

      • 형태사항

        x, 149 p.: 삽화; 27 cm

      • 일반주기명

        전북대학교 논문은 저작권에 의해 보호받습니다
        지도교수:어성국
        참고문헌 : p.125-129

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      다국어 초록 (Multilingual Abstract)

      Japanese encephalitis virus (JEV) has become one of the most common causes of viral encephalitis through the South-East Asia. Indeed, more than 60% of the world population inhabits Japanese encephalitis, and the virus is currently spreading to previously unaffected regions, such as Indonesia, Pakistan, and northern areas of Australia. Japanese encephalitis is a mosquito-borne zoonotic viral disease of the central nervous system caused by JEV, a member of the genus Flavivirus, that is symptomatically, genetically, and ecologically similar to West Nile virus and Dengue virus. It is estimated that 30,000 to 50,000 cases of JE occur each year, resulting in 10,000 to 15,000 deaths, but this actual number of cases might be underestimated. However, the exact pathogenesis of JEV-associated disease in human and mice has not yet been completely elucidated. Also, how does the innate immune response contribute to viral encephalitis and regulate adaptive immunity in vivo is still debatable. The present study on virus induced encephalitis was designed and performed to address all the questions, and ultimately to provide information on JE immunotherapeutics.
      According to our study results, the different triggering of Toll-like receptor signal array, a major innate immune receptor recognizing viral antigens strikingly regulates the contrast outcome of viral encephalitis caused by JEV. Notably, TLR3-/- mice were highly susceptible to viral encephalitis marked by enhanced viral replication, early recruitment of inflammatory CD11b+Ly6Chigh monocytes and depreciation of blood-brain barrier permeability, whereas TLR4-/- mice showed enhanced resistance to viral encephalitis with reduced immunopathological phenomena, compared to wild-type mice. Infection of cultured BMDC with JEV showed that TLR3-/- BMDC was more permissive to viral replication and showed diminished type I IFN defense. In contrast, TLR4-/- BMDC showed markedly enhanced innate defense of type I IFNs, thereby leading to reduced viral replication. Furthermore, TLR4-/- mice elicited enhanced JEV-specific CD4+ and CD8+ T cell responses as observed by higher number of IFN-?? and TNF-??-producing CD4+ and CD8+ T cells. One more interesting finding of our study is that the early expansion of CD4+CD25+Foxp3+ regulatory T cells by JEV infection was dependent on TLR4 signal pathway, thereby regulating early immune responses that might contribute to the restriction of early viral replication. Our results suggest that JEV affects CD4+CD25+Foxp3+ Treg homeostasis through TLR4 signal pathway.
      Moreover, we explored the contribution of CD4+ Th subsets, Th1, Th2, Th17 as well as Foxp3+ Treg cells, to neurological disorder during the progression of JE. Sub-lethal infection with JEV induced activation of CD4+ and CD8+ T cells with peak levels at 3 days post-infection, whereas lethal infection provided activation of CD4+ and CD8+ T cells peaked at 5 days post-infection. In particular, mice showing neurological disorder had higher proportion of activated CD4+ and CD8+ T cells than non-paralyzed mice, despite lymphopenia. Moreover, altered proportion of IL-17-producing Th17 and CD4+Foxp3+ Treg cells was observed between paralyzed and non-paralyzed mice. Interestingly, while CD4+Foxp3+ Tregs that were adoptively transferred 2 days prior to infection made the recipients vulnerable to JE, CD4+Foxp3+ Treg cells that were adoptively transferred 2 days after infection provided resistance to JE, which suggesting that CD4+Foxp3+ Treg cells elicited dual-phased roles during the progression of neurological disorder caused by JEV infection. This dual-phased role of CD4+Foxp3+ Tregs was further confirmed by using Foxp3-diphtheria toxin receptor (DTR) knock-in mice that CD4+Foxp3+ Tregs can be depleted with infection of diphtheria toxin (DT). Therefore, our results suggest that the balanced regulation between CD4+ Th subsets during the progression of JE affect the outcome of disease, thereby providing useful information to JE therapeutics and prognosis.
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      Japanese encephalitis virus (JEV) has become one of the most common causes of viral encephalitis through the South-East Asia. Indeed, more than 60% of the world population inhabits Japanese encephalitis, and the virus is currently spreading to previou...

      Japanese encephalitis virus (JEV) has become one of the most common causes of viral encephalitis through the South-East Asia. Indeed, more than 60% of the world population inhabits Japanese encephalitis, and the virus is currently spreading to previously unaffected regions, such as Indonesia, Pakistan, and northern areas of Australia. Japanese encephalitis is a mosquito-borne zoonotic viral disease of the central nervous system caused by JEV, a member of the genus Flavivirus, that is symptomatically, genetically, and ecologically similar to West Nile virus and Dengue virus. It is estimated that 30,000 to 50,000 cases of JE occur each year, resulting in 10,000 to 15,000 deaths, but this actual number of cases might be underestimated. However, the exact pathogenesis of JEV-associated disease in human and mice has not yet been completely elucidated. Also, how does the innate immune response contribute to viral encephalitis and regulate adaptive immunity in vivo is still debatable. The present study on virus induced encephalitis was designed and performed to address all the questions, and ultimately to provide information on JE immunotherapeutics.
      According to our study results, the different triggering of Toll-like receptor signal array, a major innate immune receptor recognizing viral antigens strikingly regulates the contrast outcome of viral encephalitis caused by JEV. Notably, TLR3-/- mice were highly susceptible to viral encephalitis marked by enhanced viral replication, early recruitment of inflammatory CD11b+Ly6Chigh monocytes and depreciation of blood-brain barrier permeability, whereas TLR4-/- mice showed enhanced resistance to viral encephalitis with reduced immunopathological phenomena, compared to wild-type mice. Infection of cultured BMDC with JEV showed that TLR3-/- BMDC was more permissive to viral replication and showed diminished type I IFN defense. In contrast, TLR4-/- BMDC showed markedly enhanced innate defense of type I IFNs, thereby leading to reduced viral replication. Furthermore, TLR4-/- mice elicited enhanced JEV-specific CD4+ and CD8+ T cell responses as observed by higher number of IFN-?? and TNF-??-producing CD4+ and CD8+ T cells. One more interesting finding of our study is that the early expansion of CD4+CD25+Foxp3+ regulatory T cells by JEV infection was dependent on TLR4 signal pathway, thereby regulating early immune responses that might contribute to the restriction of early viral replication. Our results suggest that JEV affects CD4+CD25+Foxp3+ Treg homeostasis through TLR4 signal pathway.
      Moreover, we explored the contribution of CD4+ Th subsets, Th1, Th2, Th17 as well as Foxp3+ Treg cells, to neurological disorder during the progression of JE. Sub-lethal infection with JEV induced activation of CD4+ and CD8+ T cells with peak levels at 3 days post-infection, whereas lethal infection provided activation of CD4+ and CD8+ T cells peaked at 5 days post-infection. In particular, mice showing neurological disorder had higher proportion of activated CD4+ and CD8+ T cells than non-paralyzed mice, despite lymphopenia. Moreover, altered proportion of IL-17-producing Th17 and CD4+Foxp3+ Treg cells was observed between paralyzed and non-paralyzed mice. Interestingly, while CD4+Foxp3+ Tregs that were adoptively transferred 2 days prior to infection made the recipients vulnerable to JE, CD4+Foxp3+ Treg cells that were adoptively transferred 2 days after infection provided resistance to JE, which suggesting that CD4+Foxp3+ Treg cells elicited dual-phased roles during the progression of neurological disorder caused by JEV infection. This dual-phased role of CD4+Foxp3+ Tregs was further confirmed by using Foxp3-diphtheria toxin receptor (DTR) knock-in mice that CD4+Foxp3+ Tregs can be depleted with infection of diphtheria toxin (DT). Therefore, our results suggest that the balanced regulation between CD4+ Th subsets during the progression of JE affect the outcome of disease, thereby providing useful information to JE therapeutics and prognosis.

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      목차 (Table of Contents)

      • Chapter 1 LITERATURE REVIEW 1
      • 1 Introduction 2
      • 2 Viral encephalitis with special emphasis on Japanese encephalitis 3
      • 3 Toll-like receptors and Viruses 4
      • 3.1 TLR Family 5
      • Chapter 1 LITERATURE REVIEW 1
      • 1 Introduction 2
      • 2 Viral encephalitis with special emphasis on Japanese encephalitis 3
      • 3 Toll-like receptors and Viruses 4
      • 3.1 TLR Family 5
      • 3.2 TLR Signaling 6
      • 3.3 Recognition of viruses by TLRs 7
      • 4 CD4 T helper cell subsets: Differentiation and role in viral diseases 8
      • 4.1 Lineage decisions of CD4 T helper cells 8
      • 4.2 The role of CD4 T helper cell subsets in viral encephalitis with special emphasis on Treg and Th17 cells 9
      • 5 Plasticity of Th17 and Treg cells and their balance in viral encephalitis 12
      • 6 Specific aims and scope of the work 13
      • References 15
      • Appendix 24
      • Chapter 2 Distinct dictation of viral encephalitis via triggering of TLR3 and TLR4 signaling pathway 29
      • 1 Introduction 31
      • 2 Materials and methods 34
      • 2.1 Animals and ethics statement 34
      • 2.2 Cells and viruses 34
      • 2.3 Antibodies and reagents 35
      • 2.4 Quantification of tissue viral burden 35
      • 2.5 Analysis of infiltrated leukocytes from the CNS 36
      • 2.6 Real-time quantitative RT-PCR for cytokines 37
      • 2.7 Primary culture and infection of dendritic cells, macrophages, and neuron cells 37
      • 2.8 Cytokines ELISA and CD4+/CD8+ T-cell responses 38
      • 2.9 Analysis of CD4+ and CD8+ T cell responses specific for JEV 39
      • 2.10 Fluorescence staining and confocal microscopy 39
      • 2.11 Evaluation of BBB permeability 40
      • 2.12 Statistical analysis 40
      • 3 Results 41
      • 3.1 Contrast modulation of protection and virus burden by signal pathway of TLR3 and TLR4 after JEV infection 41
      • 3.2 CNS inflammation and BBB permeability in TLR3 and 4-deficient mice following JEV infection 42
      • 3.3 Type I IFN and Pro-inflammatory cytokine in inflammatory and lymphoid tissues of TLR3 and 4-deficient mice following JEV infection 43
      • 3.4 Innate immune responses to JEV infection in myeloid cells derived from TLR3 and 4-deficient mice 45
      • 3.5 Adaptive immune responses specific for JEV in TLR3 and 4-deficient mice 46
      • 3.6 Enhanced inflammation associated with altered myeloid-derived cells and reduced number of CD4+Foxp3+ Treg cells in lymphoid tissue of TLR3 and 4-deficient mice 47
      • 4 Discussion 49
      • References 54
      • Appendix 62
      • Chapter 3 Interplay of CD4+ Th subset cells in Japanese encephalitis: Focused on the balance of CD4+CD25+Foxp3+ Tregs and IL-17+ROR+ Th17 cells 109
      • 1 Introduction 111
      • 2 Materials and methods 114
      • 2.1 Animals and ethics statement 114
      • 2.2 Cells and viruses 114
      • 2.3 Antibodies and reagents 114
      • 2.4 Flow cytometric analysis 115
      • 2.5 Analysis of Th1, Th2, Th17 and Treg CD4+ Th subsets 115
      • 2.6 Isolation of CD4+CD25+Treg and CD4+CD25- Th cells 116
      • 2.7 Adoptive transfer Th or Treg cells experiments 116
      • 2.8 Challenge of Dereg mice by JEV 117
      • 2.9 Statistical analysis 117
      • 3 Results 118
      • 3.1 Activation of CD4+ and CD8+ T cells after sub-lethal and lethal infection with JEV 118
      • 3.2 Kinetics of CD4+ Th subsets, Th1/Th2/Treg/Th17, in the progression of Japanese encephalitis 119
      • 3.3 Adoptive transfer of CD4+CD25+Foxp3+ Tregs at specific point progression alleviates the clinical severity of Japanese encephalitis 119
      • 4 Discussion 121
      • References 125
      • Appendix 130
      • ABSTRACT (ENGLISH) 146
      • Acknowledgement 149
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