Reprogramming of murine macrophages by the mycobacterial cord factor: = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor
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| Format: | Thesis Book |
| Language: | English |
| Published: |
Erlangen ; Nürnberg
2017
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis Inhaltsverzeichnis |
| Physical Description: | XVIII, 158 Seiten Illustrationen, Diagramme 21 cm 1 CD-ROM |
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| 245 | 1 | 0 | |a Reprogramming of murine macrophages by the mycobacterial cord factor |b = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |c vorgelegt von Alexandra Huber |
| 246 | 1 | 3 | |a Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| 246 | 1 | 1 | |a Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| 264 | 1 | |a Erlangen ; Nürnberg |c 2017 | |
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| 502 | |b Dissertation |c Friedrich-Alexander-Universität Erlangen-Nürnberg |d 2017 | ||
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| adam_text | TABLE OF CONTENTS
TABLE OF
CONTENTS.....................................................................................................................................................................I
SUMMARY............... V
ZUSAMMENFASSUNG.............................................................................................................................................................
VIII
ABBREVIATIONS.........................................................................................................................................................................
XI
INDEX OF FIGURES
................................
XVII
INDEX OF TABLES AND SUPPLEMENTARY
TABLES....................................................................................................................XVIII
1
INTRODUCTION...................................................................................................................................................................1
1.1 MACROPHAGES AND
IMMUNITY..................................................................................................................................
1
1.1.1 GENERAL MACROPHAGE
FUNCTION....................................................................................................................2
1.1.2 REPROGRAMMING OF
MACROPHAGES...............................................................................................................
3
1.2 TUBERCULOSIS
.................
4
1.2.1 CONSUMPTION - STILL AN
ISSUE?..................................................................................................................
5
1.2.2 MYCOBACTERIA AND THEIR
PAMPS..................................................................................................................
7
1.2.2.1 BACTERIAL
DNA..................................................... 8
1.2.2.2 CORD FACTOR AND ITS
RECOGNITION.........................................................................................................
9
1.3 THE ROLE OF IFNY IN
TB............................................................................................................................................14
1.4 VACCINATION AND ANTIGEN-PRESENTING
CELLS.........................................................................................................
20
2 MATERIALS AND
METHODS...........................................................................................................................................24
2.1
MATERIALS................................................................................................................................................................24
2.1.1 CHEMICALS AND
REAGENTS............................................................................................................................
24
2.1.2 KITS AND
ENZYMES........................................................................................................................................
25
2.1.3
CONSUMABLES...............................................................................................................................................
26
2.1.4 LABORATORY
EQUIPMENT..............................................................................................................................
27
2.1.5
BUFFERS..........................................................................................................................................................
28
2.1.6 CELL
CULTURE..................................................................................................................................................
30
2.1.6.1 M
EDIA..................................................................................................................................................
30
2.1.6.2 STIMULATORY
AGENTS............................................................................................................................
31
2.1.7 WESTERN BLOT ANTIBODIES AND PROTEIN
LADDER..........................................................................................
31
2.1.8 ANTIBODIES AND VIABILITY DYES FOR FLOW
CYTOMETRY....................................................................................
32
2.1.9 MATERIALS FOR MAGNETIC ACTIVATED CELL
SORTING..........................................................................................32
2.1.10 OTHER
ANTIBODIES.....................................................................................................................................
32
2.1.11 PRIMERS AND PROBES FOR
QRT-PCR.........................................................................................................
33
2.1.12 TAGS AND PROBES FOR
NANOSTRING..........................................................................................................
33
2.1.13 M
ICE...........................................................................................................................................................34
2.1.14 SOFTWARE AND ONLINE
TOOLS......................................................................................................................35
2.2
METHODS..................................................................................................................................................................
35
2.2.1 DIFFERENTIATION OF BMDMS AND
BMDCS.....................................................................................................35
2.2.2 CELL
CULTURE....................................................................................................................................................36
2.2.2.1 COATING OF CELL CULTURE PLATES WITH
GLYCOLIPIDS...............................................................................36
2.2.2 2 STIMULATION OF BMDMS AND BMDCS
................................................................................................
37
2.2.2 3 CFSE DILUTION
ASSAY............................................................................................................................
37
2.2.3 FLOW
CYTOMETRY...................................................................................................
38
2.2.4 IMMUNO
ASSAYS.............................................................................................................................................
39
2.2.4.1 IN VITRO BINDING
ASSAY........................................................................................................................39
2.24.2
ELISA....................................................................................................................................................40
2.2.5 GRIESS
ASSAY...................................................................................................................................................40
2.2.6 MTT
ASSAY.....................................................................................................................................................40
2.2.7 MOLECULAR
BIOLOGY........................................................................................................................................
41
2.2.7.1 RNA
ISOLATION.....................................................................................................................................
41
2.27.2 CDNA
SYNTHESIS..................................................................................................................................41
2.27.3
QRT-PCR..............................................................................................................................................
42
2.2 1 A
MRNA STABILITY
ASSAY..........................................................................................................................43
2.2.7.5 NANOSTRING
ELEMENTS.........................................................................................................................43
2.2.8 BIOCHEMICAL
ANALYSIS....................................................................................................................................
44
2.2.8.1 PREPARATION OF WHOLE-CELL PROTEIN
LYSATES......................................................................................
44
2.2 8.2 SDS
PAGE.............................................................................................................................................44
2.2 8.3 WESTERN
BLOT.......................................................................................................................................
45
2.2.9 SYSTEMS
BIOLOGY............................................................................................................................................45
2.2.9.1 GENOME-WIDE EXPRESSION
PROFILING.................................................................................................
45
2.2.9.2 QUALITY CONTROL AND
ANOVA..............................................................................................................46
2.2.9.3 GENE ONTOLOGY ENRICHMENT
ANALYSIS...............................................................................................
46
2.2.9.4 TFBS
ENRICHMENT................................................................................................................................
46
2.2.9.5 IN SILICO PROMOTER
ANALYSIS................................................................................................................47
2.2.10 STATISTICAL
ANALYSIS...................................................................................................................................47
3 AIM OF THE
STUDY.........................................................................................................................................................
48
4 RESULTS 50
4.1 STRUCTURAL REQUIREMENTS FOR MINCLE BINDING AND ADJUVANTICITY OF
TREHALOSE ESTERS....................................50
4.1.1 SYNTHESIS OF
COMPOUNDS............................................................................................................................51
4.1.2 MACROPHAGE AND DC
ACTIVATION.................................................................................................................52
4.1.3 MACROPHAGE ACTIVATION REQUIRES MINCLE BUT IS INDEPENDENT OF M YD
88............................................56
4.1.4 BINDING TO MINCLE-FC
PROTEIN.....................................................................................................................57
4.1.5 ACTIVITY OF STEARATE COMPOUNDS IN
VIVO...................................................................................................
59
4.2 MACROPHAGE REPROGRAMMING BY CORD FACTOR - GLOBAL EXPRESSION
PROFILING
................................................
61
4.2.1 RESPONSES TO SINGLE
STIMULI.......................................................................................................................
62
4.2.2 TDB AND TDM - COMPARISON OF NATURAL VS SYNTHETIC MINCLE
LIGAND.....................................................63
4.2.2.1 GO ENRICHMENT ANALYSIS OF TDX-INDUCED
GENES............................................................................
63
4.2.2.2 TFBS ENRICHMENT IN TDX-INDUCED
GENES........................................................................................
65
4.2.3 THE CPG
RESPONSE.......................................................................................................................................67
4.2.4 CROSSTALK BETWEEN CORD FACTOR AND TLR9 LIGAND
CPG............................................................................68
4.2.4.1 SYNERGY BETWEEN CPG AND TD
X.....................................................................................................
72
4 2.4.2 CPG-INDUCED GENES REPRESSED BY
TDX............................................................................................74
4.2.5 THE IFNY
RESPONSE.......................................................................................................................................76
4.2.5.1 GO ENRICHMENT IN THE IFNY
RESPONSE..............................................................................................76
4.2.5 2 TFBS ENRICHMENT IN THE IFNY
RESPONSE...........................................................................................77
4.2.6 CHARACTERIZATION OF IFNY AND CORD FACTOR
RESPONSE.......................................... 78
4.2.6.1 SYNERGY BETWEEN IFNY AND
TDX.......................................................................................................81
4.2.6.2 IFNY-INDUCED GENES REPRESSED IN DOUBLE STIMULATION WITH
TDX.................................................83
4.2.7 VERIFICATION BY NANOSTRING NCOUNTER
ELEMENTS.....................................................................................85
4.2.8 CORD FACTOR AND ANTIGEN PRESENTATION
..........................
88
4.2.9 ANTIMICROBIAL EFFECTORS IN IFNY-TDM
CO-STIMULATION.............................................................................92
4.2.9.1 RECEPTOR REQUIREMENT FOR G BPL
INHIBITION....................................................................................
93
4.2.9.2 GBPL REPRESSION AND IFNY SIGNALLING
.............................................................................................
95
4.2.9.3 KINETICS OF THE IFNY
RESPONSE..........................................................................................................
96
4.2.9.4 GBPL MRNA: PRIMARY TRANSCRIPT AND STABILITY OF MATURE TRANSCRIPT
........................................
97
4.2.9.5 GBPL: POSSIBLE MEDIATORS OF INHIBITION BY TD
X............................................................................
99
4.2.9.6 GBPL TRANSCRIPTIONAL REGULATION: PROMOTER
ARCHITECTURE..........................................................101
4.2.9.7 REGULATION OF GBPL BY I R F L
............
.
..............................................................................................
103
4.2.9.8 REGULATION OF GBPL BY
SOCSL.........................................................................................................
104
5
DISCUSSION................................................................................................................................................................
106
5.1 ADJUVANTS BASED ON
TDB..................................................................................................................................106
5.2 INSIGHTS INTO THE REPROGRAMMING OF RESTING AND TLR/IFNY-ACTIVATED
MACROPHAGES BY GLYCOLIPIDS
.....
109
5.3 MACROPHAGE REPROGRAMMING BY TDM AND
TDB............................................................................................109
5.3.1 COMPARISON BETWEEN TDB AND T D M
......................................................................................................
109
5.3.2 BIOLOGICAL PATHWAYS AFFECTED BY TD
X.....................................................................................................110
5.3.3 POTENTIAL TRANSCRIPTIONAL REGULATORS MEDIATING THE RESPONSE TO
TDX................................................I L L
5.4 CORD FACTOR AND CPG
CROSS-TALK.........................................................................................................................115
5.5 INTERACTION OF CORD FACTOR AND
IFNY.................................................................................................................
117
5.5.1 TDX DIFFERENTIALLY AFFECT IFNY-INDUCED INFLAMMATORY AND
HOST-PROTECTIVE RESPONSES
.....................
117
5.5.2 MECHANISMS OF GENE-SPECIFIC REGULATION OF IFNG-RESPONSE BY
TDX..................................................119
5.6 PERSPECTIVES FO R MACROPHAGE TRANSCRIPTIONAL
REPROGRAMMING...................................................................
121
6 SUPPLEMENTARY
TABLES..............................................................................................................................................124
7 DIGITAL
SUPPLEMENT....................................................................................................................................................130
8
REFERENCES..................................................................................................................................................................131
|
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| author | Huber, Alexandra |
| author_GND | (DE-588)1148343644 |
| author_facet | Huber, Alexandra |
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| building | Verbundindex |
| bvnumber | BV044697074 |
| ctrlnum | (OCoLC)1029055189 (DE-599)DNB1148356894 |
| discipline | Biologie |
| format | Thesis Book |
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| indexdate | 2024-07-10T07:59:37Z |
| institution | BVB |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-030093894 |
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| physical | XVIII, 158 Seiten Illustrationen, Diagramme 21 cm 1 CD-ROM |
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| spelling | Huber, Alexandra Verfasser (DE-588)1148343644 aut Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor vorgelegt von Alexandra Huber Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor Erlangen ; Nürnberg 2017 XVIII, 158 Seiten Illustrationen, Diagramme 21 cm 1 CD-ROM txt rdacontent n rdamedia nc rdacarrier Dissertation Friedrich-Alexander-Universität Erlangen-Nürnberg 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1148356894/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030093894&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Huber, Alexandra Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| subject_GND | (DE-588)4113937-9 |
| title | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| title_alt | Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| title_auth | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| title_exact_search | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| title_full | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor vorgelegt von Alexandra Huber |
| title_fullStr | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor vorgelegt von Alexandra Huber |
| title_full_unstemmed | Reprogramming of murine macrophages by the mycobacterial cord factor = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor vorgelegt von Alexandra Huber |
| title_short | Reprogramming of murine macrophages by the mycobacterial cord factor |
| title_sort | reprogramming of murine macrophages by the mycobacterial cord factor reprogrammierung muriner makrophagen durch den mykobakteriellen cord faktor |
| title_sub | = Reprogrammierung muriner Makrophagen durch den mykobakteriellen Cord-Faktor |
| topic_facet | Hochschulschrift |
| url | http://d-nb.info/1148356894/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030093894&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT huberalexandra reprogrammingofmurinemacrophagesbythemycobacterialcordfactorreprogrammierungmurinermakrophagendurchdenmykobakteriellencordfaktor AT huberalexandra reprogrammierungmurinermakrophagendurchdenmykobakteriellencordfaktor |
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