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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 伍安怡(Betty A. Wu-Hsieh) | |
| dc.contributor.author | Sheng-Yang Wu | en |
| dc.contributor.author | 巫聖揚 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:38:52Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-23 | |
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Diagnostic microbiology and infectious disease 61, 175-180. Yano, J., Palmer, G.E., Eberle, K.E., Peters, B.M., Vogl, T., McKenzie, A | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18902 | - |
| dc.description.abstract | 半乳糖凝集素-3廣泛地分佈在細胞內外甚至是膜上，它具有一個可辨識醣類的碳端及一個胜肽尾端。當許多文獻探討了它在自體免疫疾病、癌細胞轉移、細菌和寄生蟲感染、以及纖維化疾病中的角色，它在真菌感染中的重要性卻鮮少有人著墨。真菌感染是一種隱型殺手──據臨床統計指出，即便接受了抗真菌藥物的治療，真菌造成的全身性感染患者仍有高達一半的死亡率，顯示如何控制真菌感染及提供該感染有效治療的方法是全球的重要議題。而我的研究顯示了內生性的半乳糖凝集素-3會負調控先天免疫細胞抗組織胞漿菌及白色念珠菌的感染。
鮮少有人在組織胞漿菌感染時引發症狀，但若是免疫低落或免疫不全的病人在感染後卻極易發展成全身性感染，進而造成死亡。當肺部組織胞漿症的清除需仰賴第一型和第十七型免疫反應，我的研究指出半乳糖凝集素-3會負調控樹突細胞生成IL-17A相關的細胞激素之能力，進而造成CD4 T細胞和嗜中性顆粒球生成IL-17A的能力下降。IL-17A的存在可協助IFN-γ活化巨噬細胞、促使巨噬細胞內組織胞漿菌之生長被抑制。相較於一般小鼠，半乳糖凝集素-3基因剔除的小鼠感染後體內真菌量也因有較高量IL-17A生成而下降。以靜脈注射方式將樹突細胞送入感染的小鼠體內顯示了半乳糖凝集素-3對宿主IL-17A免疫反應和其體內真菌清除之調控乃是經由抑制樹突細胞生成細胞激素之能力造成。 白色念珠菌分佈在人類的皮膚和黏膜表面，是一種伺機性的雙性型真菌。在台灣醫療照護機構內全身性感染案例中，念珠菌感染佔了第一位。白色念珠菌之感染仰賴嗜中性顆粒球進行清除。我們發現未刺激前人類和小鼠的嗜中性顆粒球的半乳糖凝集素-3僅表現在胞內，而白色念珠菌刺激才誘使其在細胞表面被偵測到。當細胞透過CR3辨識調理過的白色念珠菌後，會透過活化磷酸激酶Syk促使細胞生成活性氧，直接毒殺真菌。半乳糖凝集素-3則會抑制Syk的活化，造成毒殺能力下降。共免疫沉降法和螢光染色顯示胞內的半乳糖凝集素-3可直接和Syk作用。而半乳糖凝集素-3基因剔除的小鼠，比起一般小鼠，在全身性白色念珠菌感染後體內真菌數量較低、腎臟病變程度也減緩、死亡率顯著下降。進一步以靜脈注射方式將嗜中性顆粒球送入感染的小鼠體內則證明了半乳糖凝集素-3是藉由調控嗜中性顆粒球的功能而抑制宿主抗真菌之能力。不僅是對實驗用菌株，比較了從病患血液中取得的臨床菌株，我們發現半乳糖凝集素-3也可以抑制嗜中性顆粒球毒殺這些臨床菌株的能力。人類嗜中性顆粒球在半乳糖凝集素-3拮抗劑處理後或以siRNA轉染的方式減少半乳凝集素-3基因表現後，其負責毒殺真菌的活性氧生成量也顯著上升。我們的研究提出了抑制嗜中性顆粒球胞內的半乳糖凝集素-3是一種可行的全身性白色念珠菌治療方式。 | zh_TW |
| dc.description.abstract | Galectin-3 (Gal3), belonging to the galectin family, has an evolutionarily conserved C-terminal carbohydrate-recognition domain and a unique N-terminal peptide. While it has been reported to modulate host response to autoimmune diseases, cancer metastasis, bacterial and parasite infections, and fibrosis, there are few studies address its role in fungal infection. Fungal infection as a hidden killer for human beings on the Earth leads to more than 50% mortality when disseminated even in patients with anti-fungal treatment. How to control its spread and provide a promising therapeutic strategy are universal issues. My studies on dimorphic Histoplasma capsulatum infection and opportunistic Candida albicans infection reveal the importance of endogenous gal3 in innate cell response to fungi.
While most people live in endemic area infected by Histoplasma without any symptoms, its infection easily disseminates in immuno-depressed or immunocompromised patients and leads to death. The clearance of pulmonary Histoplasma infection is dependent on both Th1 and Th17 responses. My study shows that gal3 negatively regulated bone marrow-derived and splenic dendritic cell IL-17A-axis cytokine production. The level of IL-17A production by both CD4 T cells and neutrophils was higher in gal3-/- mice after systemic Histoplasma infection. IL-17A alone or combined with IFN-γ activates macrophage to inhibit the growth of intracellular Histoplasma. Gal3-/- mice had lower fungal burden in the spleen compared to gal3+/+ mice. Neutralizing IL-17A increased fungal burden in gal3-/- mice to a level comparable to that in gal3+/+ mice, while neutralizing IFN-γ increased fungal burden in both gal3+/+ and gal3-/- mice. Adoptive transfer of dendritic cells showed that cell intrinsic gal3 in dendritic cells negatively regulated host IL-17A-axis cytokine production and fungal clearance. In this study, we demonstrated a negative role of intrinsic gal3 in dendritic cell IL-17A-axis cytokine production as well as in fungal clearance. Candida albicans is an opportunistic dimorphic fungus, which is a commensal in the mucosa surface and skin in most humans. Invasive candidiasis is the first leading overall health-associated infection as well as bloodstream infection in intensive care units in Taiwan. Neutrophils are the major effector cells to clear fungal infection. We show that unstimulated human and mouse neutrophils express galectin-3 intracellularly, and it becomes detectable on the cell surface after stimulation by opsonized Candida. Upon CR3 engagement with opsonized Candida, galectin-3 downregulates Syk-mediated ROS production and subsequent killing of fungus. Co-immunoprecipitation and immunofluorescence staining reveal that cytosolic gal3 physically interacts with Syk. Moreover, galectin-3 deficiency ameliorates systemic candidiasis by reducing fungal burden, renal pathology, and mortality. Adoptive transfer experiments demonstrate that cell intrinsic gal3 negatively regulates neutrophil effector function in candidiasis. Additionally, the effect of galectin-3 on neutrophil anti-Candida function and host resistance to candidiasis is tested in clinical isolates. Treatment with galectin-3 antagonist or siRNA enhances human neutrophil ROS production. Our work raises the possibility that blocking gal3 in neutrophils may be a promising therapeutic strategy for treating systemic candidiasis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:38:52Z (GMT). No. of bitstreams: 1 ntu-105-D00449001-1.pdf: 5334375 bytes, checksum: 1b74224329a5cda84544686d487ec8f9 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 中文摘要 1
Abstract 3 Chapter 1. Introduction 11 Part I. Galectin-3 as an immunoregulatory mediator 12 Part II. Exogenous and endogenous galectin-3 13 Part III. Fungal infections as hidden killers for humans 14 Part IV. Histoplasma capsulatum 16 A. Histoplasma capsulatun and histoplasmosis 16 B. Host defense Histoplasma infection 17 C. Macrophages as both host cells of and effector cells to clear Histoplasma 18 D. Th17 immunity 18 Part V. Candida albicans 19 A. Candida infection and host defense 19 B. Neutrophil anti-Candida functions 20 C. Neutrophil receptors to recognize Candida albicans 21 D. NADPH oxidase-mediated respiratory burst in neutrophils 22 Chapter 2. Specific aims 24 Aim 1: To study the role of endogenous galectin-3 in systemic histoplasmosis 24 1-1. To study the role of endogenous galectin-3 in dendritic cell cytokine production in response to Histoplasma infection 24 1-2. To investing whether and how galectin-3 modulates T cell responses to Histoplasma infection 24 Aim 2: To study the role of endogenous galectin-3 in systemic candidiasis 24 2-1. To study the role of endogenous galectin-3 in neutrophil fungicidal activity against Candida 24 2-2. To study the mechanism by which galectin-3 regulates neutrophil fungicidal activity 24 2-3. To assess the role of endogenous galectin-3 in systemic candidiasis 24 Chapter 3. Materials and Methods 25 Part I. Materials 26 A. Mice and ethics statement 26 B. Antibodies used in flow cytometric analysis, immunofluorescence staining and Western blotting 26 C. ELISA 28 D. Primer sequences used in quantitative RT-PCR 29 E. Buffers and Culture mediums 30 Part II. Methods 33 A. Hstoplasma capsulatum infection 33 B. Candida albicans infection 40 Chapter 4. Results 45 Part I. The role of gal3 in dendritic cell response to Histoplasma infection 46 1. Gal3 negatively regulates the production of IL-17A-axis cytokines by dendritic cells after Histoplasma stimulation 46 2. Gal3 negatively regulates Th17 differentiation after infection 47 3. IL-23 stimulates neutrophils to produce IL-17A 48 4. Gal3-mediated inhibition of fungal clearance is through negative regulation of IL-17A response 50 5. IL-17A activates macrophages to inhibit intracellular growth of Histoplasma 50 6. The presence of gal3 in dendritic cells downregulates IL-17A-axis cytokines and diminishes the ability of the host to clear fungal infection 51 Part II. The role of gal3 in neutrophil response to Candida infection 52 1. Upregulation of gal3 expression in neutrophil response to opsonized Candida 52 2. Gal3 negatively regulates neutrophil ROS production, but not anti-microbial peptide expression and NETosis and subsequent killing of Candida 52 3. Gal3 negatively regulates CR3, but not dectin-1 and Fc receptor, downstream ROS-dependent killing of Candida in neutrophils 54 4. Gal3 physically interacts with Syk and downregulates ROS production through negative regulation of Syk and PKCβ2 phosphorylation 55 5. Gal3-/- mice are more resistant to systemic Candida infection 56 6. Gal3 deficiency enhances fungicidal activity of renal infiltrating neutrophils by increasing ROS production 57 7. The negative effect of gal3 on host defense against systemic candidiasis is dependent on CR3 but not dectin-1 58 8. Neutrophil intrinsic gal3 suppresses host defense against Candida 58 9. The negative effect of gal3 on neutrophil anti-Candida functions is generalizable to clinical isolates 59 10. Gal3 negatively regulates human neutrophil ROS response to opsonized Candida 60 Chapter 5. Discussion 61 Part I. Endogenous gal3 and systemic histoplasmosis 62 Part II. Endogenous gal3 and systemic candidiasis 67 Part III. The compartment where gal3 is determines its effect on phagocyte cellular responses 75 Chapter 6. References 77 List of Figures Chapter 7. Figures 93 Figure 1. Gal3 negatively modulates IL-17A-axis cytokine production in dendritic cell response to Histoplasma stimulation. 94 Figure 2. Gal3 downregulates the level of IL-17A-axis cytokines in spleen after systemic Histoplasma infection. 96 Figure 3. The presence of endogenous gal3 reduces the ability of splenic dendritic cells to express IL-17A-axis cytokines in systemic Histoplasma infection. 98 Figure 4. Endogenous gal3 suppresses Th17 and enhances Th1 responses to systemic Histoplasma infection. 100 Figure 5. Intrinsic gal3 is not involved in naive CD4+ T cell differentiation toward Th1 or Th17 cells. 102 Figure 6. Higher numbers of splenic CD4+ T cells and neutrophils in gal3-/- mice produce IL-17A after systemic Histoplasma infection than in gal3+/+ mice. 104 Figure 8. Thioglycollate-elicited neutrophils produce IL-17A in response to IL-23 stimulation. 108 Figure 9. Gal3 negatively regulates c-Raf-mediated lL-23 production by dendritic cells in response to Histoplasma. 110 Figure 10. Gal3 reduces host ability to clear systemic Histoplasma infection. 112 Figure 11. While IFNγ contributes to fungal clearance in both gal3+/+ and gal3-/- mice, IL-17A participates only in gal3-/- mice defense against systemic Histoplasma infection. 114 Figure 12. IL-17A enhances both IFN-γ-dependent and -independent inhibitory effects of macrophages on the growth of intracellular Histoplasma. 116 Figure 13. Adoptive transfer of gal3-/- dendritic cells promotes IL-17A response and fungal clearance. 118 Figure 14. Opsonized Candida upregulates cytosolic gal3 expression in neutrophils. 120 Figure 15. Cytosolic gal3 does not specifically co-localize with engulfed Candida. 122 Figure 16. Cytosolic gal3 does not interact with engulfed Candida. 124 Figure 17. Gal3 negatively regulates ROS-dependent killing of Candida by neutrophil. 126 Figure 18. Gal3 has only marginal effect on neutrophil expression of antimicrobial peptides. 128 Figure 19. Gal3 is not involved in Candida-induced NET formation. 130 Figure 20. Complement receptor 3 mediates neutrophil killing of opsonized Candida. 132 Figure 21. Dectin-1 and Fc receptor are not involved in neutrophil anti-Candida function. 134 Figure 22. Dectin-1 is involved in bone marrow neutrophil ROS production in response to unopsonized zymosan but not to opsonized zymosan and Candida. 136 Figure 23. Gal3 negatively regulates CR3-mediated killing of Candida by neutrophils. 138 Figure 24. Gal3 does not interacts with CR3 before and after Candida stimulation. 140 Figure 25. The negative effect of gal3 on neutrophil anti-Candida function is not dependent on dectin-1. 142 Figure 26. Neutrophil ROS response to Candida is dependent on Syk and PKCβ2 activation. 144 Figure 27. CR3 engagement activates Syk in neutrophil response to opsonized Candida, while CR3 and dectin-1 are not involved in PKCβ2 activation. 146 Figure 28. Syk and PKCβ2 activation in neutrophil response to Candida is negatively regulated by gal3. 148 Figure 29. Gal3 physically interacts with Syk in neutrophil response to opsonized Candida. 150 Figure 30. Gal3 does not associate with PKCβ2 after stimulation with opsonized Candida. 152 Figure 31. The level of gal3 in sera increases in response to systemic Candida infection. 154 Figure 32. gal3-/- mice sustain less renal dysfunction compared to gal3+/+ mice after systemic Candida infection . 156 Figure 33. Gal3-/- mice exhibit less severe histopathology in the kidney than gal3+/+ mice after systemic Candida infection. 158 Figure 34. The presence of gal3 exacerbates the severity of systemic Candida infection. 160 Figure 35. More number of Candida hyphae in kidney of infected gal3+/+ mice after systemic Candida infection compared to gal3-/- mice. 162 Figure 36. The negative effect of gal3 in host defense against Candida infection is through neutrophil production of ROS. 164 Figure 37. Gal3 does not affect renal and blood neutrophil recruitment after systemic Candida infection. 166 Figure 38. Gal3 negatively regulates neutrophil activation after Candida infection. 168 Figure 39. Gal3 does not affect neutrophil-attracting chemokine expression after Candida infection. 170 Figure 40. The negative effect of gal3 on host defense against systemic candidiasis is dependent on CR3 but not dectin-1. 172 Figure 41. Adoptive transfer of gal3-/- neutrophils reduces fungal burdens in recipient mice. 174 Figure 42. Adoptive transfer of gal3-/- littermate neutrophils reduces fungal burdens in recipient mice. 176 Figure 43. Adoptive transfer of gal3-/- neutrophils reduces fungal burdens in ncf-1-/- recipient mice. 178 Figure 44. To test the effect of gal3 on neutrophil response to Candida clinical isolates. 180 Figure 45. Inhibiting or silencing gal3 upregulates ROS production in human neutrophil response to opsonized Candida. 182 | |
| dc.language.iso | en | |
| dc.title | 半乳糖凝集素-3對先天免疫細胞抗真菌功能之調控 | zh_TW |
| dc.title | The Immunomodulatory Role of Galectin-3 in Innate Immune Response to Fungal Infection | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 劉扶東(Fu-Tong Liu),陳宜君(Yee-Chun Chen),繆希椿(Shi-Chuen Miaw),林錫賢(Hsi-Hsien Lin) | |
| dc.subject.keyword | 半乳糖凝集素-3,樹突細胞,嗜中性顆粒球,組織胞漿菌,白色念珠菌,細胞激素,活性氧,磷酸激?, | zh_TW |
| dc.subject.keyword | galectin-3,dendritic cell,neutrophil,Histoplasma,Candida,IL-17,IL-23,ROS,Syk,TD139, | en |
| dc.relation.page | 183 | |
| dc.identifier.doi | 10.6342/NTU201603518 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-08-23 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 免疫學研究所 | zh_TW |
| 顯示於系所單位： | 免疫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-105-1.pdf 目前未授權公開取用 | 5.21 MB | Adobe PDF |
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