Toll-like receptors (TLR)

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Table of contents

SUMMARY
ACKNOWLEDGMENTS
TABLE OF CONTENTS
LIST OF FIGURES
LIST OF TABLES
LIST OF ANNEX CONTENT
ABBREVIATIONS
I. GENERAL INTRODUCTION
1.1 Malaria – overview
1.1.1 Female Anopheles mosquitoes – vector of malaria
1.1.2 History of malaria, mosquito-vector discovery and vector control
1.1.3 Why is Africa the most malaria endemic continent – what makes a competent mosquito vector? .
1.1.4 The complex lifecycle of Plasmodium parasite in vertebrate and mosquito
1.1.5 Two bottlenecks of Plasmodium development in mosquito vector
1.2 Microbial sensing by the immune system
1.2.1 Basis of microbial immune sensing and evolution
1.2.2 LRR domain proteins in immunity
1.2.2.1 LRR proteins in the innate immune system
1.2.2.1.1 Drosophila Toll receptors
1.2.2.1.2 Toll-like receptors (TLR)
1.2.2.1.3 Nucleotide-binding leucine-rich repeat receptors
1.2.2.1.4 Plant LRRs
1.2.2.2 LRR-coding receptors in adaptive-like immunity of jawless vertebrates
II. CURRENT KNOWLEDGE, GAPS AND OBJECTIVES
2.1 Natural resistance to Plasmodium highlighted a family of LRR genes termed APL1 (Anopheles Plasmodium-responsive leucine-rich repeat)
2.2 APL1 functional activity and the mosquito complement system
2.3 Scope of the thesis
III. RESULTS
3.1 APL1C protein is a pathogen binding factor for the midgut ookinete stage of Plasmodium
3.1.1 Blood feeding induces an extracellular layer of APL1C surrounding the midgut
3.1.2 APL1C presence on the basal side of the midgut epithelium is microbiome independent
3.1.3 APL1C binds to Plasmodium ookinetes exiting the basal side of the midgut epithelium
3.1.4 LRR proteins bind autonomously to the ookinete surface (coll.: C. Lavazec, Institut Cochin, Paris) .
3.1.5 Phagocytic hemocytes are required for wildtype APL1C levels in the hemolymph
3.1.6 Nitration pathway activity is required for full APL1C abundance in hemolymph
3.2 APL1C protein is a pathogen binding factor for the hemocoel sporozoite stage of Plasmodium
3.2.1 Sporozoites affect APL1C protein abundance
3.2.2 APL1C activity in the hemocoel limits sporozoite invasion of salivary glands
3.2.3 APL1C binds to free Plasmodium sporozoites in the mosquito hemolymph LE OF
.4 APL1C protective activity against sporozoites does not require the complement 109 proteins TEP1 or TEP3
3.3 Implication of the APL1 LRR family in immune signal transduction
3.3.1 APL1A and APL1C gene silencing in A. coluzzii
3.3.2 Kinetics of APL1A and APL1C silencing
3.3.3 RNAseq and bioinformatic analysis
3.3.4 qPCR validation of the RNAseq gene candidates.
3.3.5 APL1C controls expression of immune-like genes in the mosquito
IV. DISCUSSION
4.1 Dual functionality for APL1C as guard and PRR-like factor
4.2 The HdMvs, a source of secreted APL1C, mediated by the nitration pathway?
4.3 APL1C presence in hemolymph at the basal side of the midgut epithelium is not PAMP dependent
4.4 The sophisticated sporogony control by APL1C
4.5 Whole transcriptome analysis reveals differential signalling function of APL1 genes
V. CONCLUDING REMARKS AND FUTURE PERSPECTIVES
VI. MATERIALS AND METHODS
REFERENCES
ANNEX
ABSTRACT