Characterisation of toll like receptor 8 as a new innate immune receptor for mycobacterium tuberculosis

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Characterisation of toll like receptor 8 as a new innate immune receptor for mycobacterium tuberculosis

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! ! ! CHARACTERISATION!OF!TOLL.LIKE!RECEPTOR!8!AS!A!NEW! INNATE!IMMUNE!RECEPTOR!FOR!MYCOBACTERIUM, TUBERCULOSIS! ! ! ! OH!SEEN!HUEY!OLIVIA! (BSc.!(Hons.),!NUS)! ! ! ! A!THESIS!SUBMITTED!! FOR!THE!DEGREE!OF!DOCTOR!OF!PHILOSOPHY! ! ! DEPARTMENT!OF!MICROBIOLOGY! ! ! NATIONAL!UNIVERSITY!OF!SINGAPORE! 2012! ! ! ! ! Acknowledgements! ! Acknowledgements. First! and! foremost,! I! would! like! to! offer! my! sincere! gratitude! to! my! supervisor! and!number!one!blood!donor,!A/Prof!Paul!MacAry!for!his!guidance!and!support! whilst!allowing!me!room!to!try!things!my!own!way.!!Many!thanks!also!to!Fatimah! and! Chien! Tei! for! facilitating! my! work! through! the! smooth! running! of! the! laboratory.!! This! work! would! not! have! been! possible! without! the! contribution! of! the! following!people!–!Sonia!Davila!and!Martin!Hibberd!from!the!Genomic!Institute! of! Singapore! for! genomic! information;! Dr! Andres! Floto,! Krisztina! Hegyi,! Catherine! Schaffner,! Karen! Brown,! Lucy! Hepburn,! and! Sarah! Coulter! from! the! Cambridge! Institute! for! Medical! Research! for! pH! data! and! transfection! experiments!on!human!macrophages;!Dr!Sylvie!Alonso,!Lin!Wenwei!and!Vanessa! Koh!for!work!on!MTB;!Dr!Seah!Geok!Teng!for!the!various!mycobacteria!species;! Prof!Ng!Mah!Lee!and!Yap!Han!for!electron!microscopy!work;!!Prof!Mike!Kemeny! and!Christopher!Yang!!for!cloning!the!TLR8.2!receptor;!and!A/Prof!Lu!Jinhua!and! Jason!Goh!for!the!TLR8!WT!plasmid!and!techniques!for!the!dual!luciferase!assay.!! Life!in!the!laboratory!would!not!have!been!so!enjoyable!without!the!company!of! my! fellow! lab! members,! especially! Voja,! Adrian,! Yanting,! Enwei,! and! Nurhuda.!! Thank! you! for! your! fun! and! laughter,! as! well! as! your! precious! blood.! Special! thanks! go! to! Adrian! for! proofreading! my! thesis.! ! I! would! also! like! to! thank! my! family!and!friends!for!their!continuous!support!and!encouragement.! ! ! ! ii! ! ! Table!of!Contents! ! Table.of.Contents. ! ! . Acknowledgements ii! Table!of!Contents iii! Summary .viii! List!of!Figures ix! List!of!Tables xii! Abbreviations .xiii! List!of!Publications xvii! Chapter!1.!Introduction 1! 1.1! Mycobacterium,tuberculosis 2! 1.1.1! Mycobacteria 2! 1.1.2! Human!Exposure!to!Mycobacteria 3! 1.1.3! Epidemiology!of!TB . 3! 1.1.4! Pathogenesis!of!TB . 4! 1.2! Innate!Immunity!to!Mycobacteria 6! 1.2.1! Host!Genetics!and!Immunity!to!Mycobacteria . 6! 1.2.2! Innate!Immunity!to!MTB,Infection . 8! 1.2.3! Uptake!and!Recognition!of!Mycobacteria!by!Macrophages .10! 1.2.4! Intracellular!Fate!of!MTB 11! 1.3! The!Role!of!Toll.Like!Receptors!in!Mycobacterium!Infections 12! ! 1.3.1! Toll.Like!Receptors .12! 1.3.2! TLRs!in!Mycobacterium!Infections .19! 1.3.3! TLR!Polymorphisms!and!Susceptibility!to!TB .24! 1.3.4! Genetic!Association!of!TLR8!in!Pulmonary!TB 27! iii! ! ! Table!of!Contents! ! 1.4! Toll.Like!Receptor!8 .29! 1.4.1! TLR8!Biology 29! 1.4.2! Agonists!of!TLR8 .30! 1.4.3!! Expression!and!Localisation!of!TLR8 33! 1.4.4! Immune!Functions!Associated!with!TLR8 .34! 1.4.5! TLR8!in!Bacterial!Infections 35! 1.4.6! Genetic!Variation!in!Human!TLR8 36! 1.5! Aims!of!this!Study 37! Chapter!2.!Materials!and!Methods 39! 2.1! Solutions!and!Buffers .40! 2.1.1! Buffers!for!Cell!Culture!and!Isolation!of!Primary!Cells 40! 2.1.2! Buffers!for!Mycobacteria!Culture!and!Work 40! 2.1.3! Buffers!for!SDS.PAGE!and!Western!Blot 41! 2.1.4! Buffers!for!DNA!Gel!Electrophoresis 42! 2.1.5! Buffers!for!Metabolic!Labeling .42! 2.1.6! Buffers!for!Confocal!Microscopy 43! 2.1.7! Buffers!for!Electron!Microscopy 43! 2.2! Reagents 44! 2.2.1! TLR!Agonists .44! 2.2.2! Antibodies 44! 2.2.3! Plasmids .44! 2.3! Primary!Cells!and!Cell!Culture .47! 2.3.1! Cell!Culture 47! 2.3.2! Differentiation!of!THP1!and!THP1!Blue!cell!lines 47! 2.3.3! Isolation!and!Culture!of!Primary!Human!Macrophages 48! 2.4! Mycobacteria!Culture .49! ! iv! ! ! Table!of!Contents! ! 2.4.1! Mycobacteria!Culture .49! 2.4.2! Alexa!Fluor®!647!Labelling!of!BCG 49! 2.4.3! Generation!of!Mycobacterial!Homogenates 50! 2.4.4! Treatment!of!BCG!Homogenates!for!Ligand!Identification 50! 2.4.5! Isolation!of!BCG!RNA 51! 2.4.6! Isolation!of!BCG!DNA 51! 2.4.7!! Isolation!of!BCG!Proteins 52! 2.4.8! 16S!derived!phylogeny!of!the!Mycobacterium!genus .53! 2.5! Genotyping!TLR8!M1V!Frequencies 53! 2.6! Transfection .54! 2.6.1! Lipofectamine!Transfection!of!HEK293T!cells 54! 2.6.2! Accell!TLR8!small!interfering!RNA!transfection!in!THP1 .54! 2.6.3! Transfection!in!primary!macrophages 55! 2.7! Analysis!of!NFκB!activation .55! 2.7.1! Quantification!of!NFκB!activation!in!THP1!Blue!cells 55! 2.7.2! Dual.Luciferase!Reporter!Assay 55! 2.8! Analysis!of!TLR8!Transcripts!and!Proteins 56! 2.8.1! Signal!Peptide!Prediction 56! 2.8.2! RT.PCR 57! 2.8.3! SDS.PAGE!and!Western!Blot 58! 2.8.4! Analysis!of!TLR8!Glycosylation 59! 2.9! Imaging .60! 2.9.1! Confocal!Microscopy .60! 2.9.2! Transmission!Electron!Microscopy 60! 2.10! Infection!Studies 61! 2.10.1! Mycobacteria!Killing!Assay!By!Quantification!of!CFU 61! 2.10.2! Mycobacteria!Killing!Assay!by!Luminescent!Reporter 62! ! v! ! ! Table!of!Contents! ! 2.10.3! Analysis!of!BCG!Phagolysosome!Maturation 62! 2.10.4! Measurement!of!Phagosomal!pH .63! 2.10.5! Bioplex!Cytokine!Array 63! 2.10.6! Bioplex!Phosphoprotein!Array .64! 2.10.7! Prostaglandin!E2!Analysis .65! 2.11! Statistical!Analysis 65! Chapter!3.!Results!I .66! 3.1! Introduction .67! 3.2! In,Silico,Analysis!of!5’!Polymorphisms .70! 3.3! TLR8!M1V!is!the!Predominant!Variant!in!the!Singaporean!Population 70! 3.4! The! Regulation! of! TLR8! Expression! is! Unaffected! by! the! 5’! Regulatory! and! M1V!Polymorphisms .75! 3.5! The!TLR8!M1V!Variant!Uses!An!Alternative!Start!Codon 78! 3.6! TLR8!WT!and!M1V!Differ!in!the!N.Region!of!Their!Signal!Peptide .81! 3.7! TLR8!WT!and!M1V!Variants!Undergo!Similar!Processing!in!the!ER .85! 3.8! TLR8!WT!and!M1V!Both!Traffic!Via!the!Common!Secretory!Pathway .90! 3.9! TLR8!WT!and!M1V!Both!Contain!an!Intracellular!Targeting!Motif .92! 3.10! TLR8!Variants!Have!Differential!Preferences!for!Endosomal!Compartments94! 3.11! TLR8!M1V!Shows!a!Stronger!NFκB!Response .99! Chapter!4.!Results!II . 107! 4.1! Introduction 108! 4.2! Establishing! THP1! as! an! Experimental! Model! for! Studying! Mycobacteria! Recognition!by!TLR8 108! 4.3! TLR8!is!Recruited!to!the!Mycobacterial!Phagosome . 112! 4.4! TLR8!is!Involved!in!Mycobacterial!Sensing . 114! 4.5! TLR8!is!a!Mycobacteria!Sensor . 117! ! vi! ! ! Table!of!Contents! ! 4.6! The!Generation!of!the!TLR8.2!Fusion!Receptor 119! 4.7! The!Expression!of!the!TLR8.2!Fusion!Receptor 121! 4.8! Ligand!Screening!with!the!TLR8.2!Fusion!Receptor . 123! 4.9! The!Identification!of!the!Mycobacteria!Derived!Ligand!for!TLR8 . 125! 4.10! Reduced! TLR8! Levels! Lead! to! Impaired! Mycobactericidal! Activity! in! Monocytic!Cells . 129! 4.11! Discussion 132! Chapter!5.!Results!III . 136! 5.1! Introduction 137! 5.2! The!M1V!Polymorphism!Affects!the!Kinetics!of!Phagosome!Maturation 137! 5.3! The!Mycobacteria!Phagosomes!of!TLR8!M1V!Macrophages!Are!Characteristic! of!Bacteriocytic!Phagosomes 143! 5.4! TLR8! M1V! Expressing! Macrophages! Have! Enhanced! Intracellular! Mycobactericidal!Activity 147! 5.5! Molecular! Mechanisms! for! Functional! Differences! Between! TLR8! WT! and! TLR8!M1V . 151! 5.6! Effector!Mechanisms!for!Functional!Differences!Between!TLR8!WT!and!TLR8! M1V 153! 5.7! An!Analysis!of!the!Cyclooxygenase!2!Pathway 156! 5.8! TLR8!M1V!Transfection!‘Rescues’!WT!Primary!Macrophages 160! 5.10! Discussion 163! Chapter.6:.Discussion 169! Chapter.7 References . 181! ! ! vii! ! ! Summary! ! Summary. Previous! reports! have! implicated! the! chemokine! receptor! CCR5! and! Toll.like! receptors! TLR2! and! TLR4! in! the! innate! immune! recognition! of! Mycobacterium, tuberculosis, (MTB).! In! this! study,! we! provide! comprehensive! genetic,! biochemical,! cellular! and! mechanistic! data! linking! intracellular! TLR8! to! the! detection! and! host! response! to! pathogenic! mycobacteria.! Natural! polymorphisms! in! TLR8! have! been! implicated! in! susceptibility! or! protection! from! pulmonary! MTB! infections! in! Indonesian! and! Russian! cohorts.! Here! we! demonstrate! that! the! protective! polymorphism! termed! rs3764880! (M1V)! generates! a! functional! TLR8! receptor! variant! with! an! altered! signal! peptide,! causing! the! trafficking! of! TLR8! to! early! rather! than! late! endosomes.! The! protective! TLR8! polymorphism! results! in! increased! inflammatory! cytokine! release,!promotes!phagosomal!acidification!and!enhances!intracellular!killing!of! MTB.! These! results! indicate! that! the! TLR8! receptor! pathway! may! represent! a! new!target!for!pharmacological!or!immunological!manipulation!in!MTB,infection. ! ! viii! ! ! List!of!Figures! ! List.of.Figures. Introduction! Figure!1.1! Natural!progression!of!MTB!infection! Figure!1.2! TLR!trafficking!and!signalling! 17! Figure!1.3! Schematic!of!TLR8!polymorphisms! 28! Figure!1.4! Structure!of!synthetic!TLR8!agonists!in!comparison! to!purine!nucleotides!adenosine!and!guanosine! ! ! 33! Figure!3.1! Signal!sequence!structure!and!ER!insertion!! 69! Figure!3.2! Sequence!analysis!for!TLR8!SNP!rs3764880! 72! Figure!3.3! Allelic! frequencies! of! SNP! rs3764880! in! various! populations! ! TLR8! mRNA! expression! levels! in! primary! human! macrophages! ! TLR8! protein! expression! levels! in! primary! human! macrophages! ! Generation!of!TLR8!M1,4V! 74! Expression! of! TLR8! variants! in! transfected! HEK293T!cells!!! ! Signal!peptide!prediction!for!TLR8!variants! 80! Schematic! representation! of! the! signal! peptide! region!of!TLR8! ! Prediction!of!glycosylation!sites!present!in!TLR8! 84! Sensitivity!of!TLR8!variants!to!digestion!by!Endo!H! and!Pngase!F! ! Kinetics!of!TLR8!processing!in!the!ER! 88! TLR8! localisation! with! respect! to! the! ER! and! Golgi! apparatus!! ! 91! ! 8! Results!I! Figure!3.4! Figure!3.5! Figure!3.6! Figure!3.7! Figure!3.8! Figure!3.9! Figure!3.10! Figure!3.11! Figure!3.12! Figure!3.13! ! 76! 77! 79! 83! 86! 89! ix! ! ! Figure!3.14! Figure!3.15! Figure!3.16! Figure!3.17! Figure!3.18! ! List!of!Figures! ! The!tyrosine!based!YXXΦ!sorting!motif!is!present!in! TLR7,!TLR8!and!TLR9! Localisation! of! TLR8! variants! with! respect! to! endolyosomal!compartments!! ! Differential! distribution! of! TLR8! variants! in! early! and!late!endsomes!! ! The! TLR8! M1V! variant! shows! altered! intracellular! localisation!! ! TLR8!M1V!induces!higher!levels!of!NFκB!activation! compared!to!WT! ! 93! 95! 96! 98! 100! Results!II! Figure!4.1! THP1! Blue! cells! have! functional! TLR2,! TLR4! and! TLR8!responses! ! NFκB! signalling! is! activated! in! BCG! infected! THP1! Blue!cells! ! TLR8!is!found!in!association!with!the!mycobacteria! phagosome! ! ! Establishing! siRNA! knockdown! of! TLR8! in! THP1! Blue!cells! ! TLR8! mediates! the! immune! recognition! of! mycobacteria! ! TLR8!is!a!general!sensor!for!mycobacteria! 110! 120! Figure!4.8! Schematic! representation! of! the! TLR8.2! fusion! construct! ! Surface!expression!of!the!TLR8.2!fusion!receptor! Figure!4.9! Ligand!screening!with!the!TLR8.2!fusion!receptor! 124! Figure!4.10! The!identification!of!mycobacterial!PAMPs!with!the! TLR8.2!fusion!receptor! ! Mycobacteria!derived!RNA!and!proteins!are!ligands! for!TLR8! ! 126! Figure!4.2! Figure!4.3! Figure!4.4! Figure!4.5! Figure!4.6!! Figure!4.7! Figure!4.11! ! 112! 113! 115! 116! 118! 122! 128! x! ! ! Chapter!7:!References! ! Harding,! C.V.,! and! Boom,! W.H.! (2010).! Regulation! of! antigen! presentation! by! Mycobacterium!tuberculosis:!a!role!for!Toll.like!receptors.!Nat!Rev!Microbiol,8,! 296.307.! 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Triacyl$lipopeptides$ Bacteria$and$mycobacteria$ Lipoteichoic$acid$ Group$B$Streptococcus$ Peptidoglycan$ Gram)positive$bacteria$ Porins$ Neisseria$ Lipoarabinomannan$ Mycobacteria$ Flagellin$ Flagellated$bacteria$ CpG$DNA$ Bacteria$and$mycobacteria$ ' Fungus' Zymosan$ Saccharomyces0cerevisiae$ Phospholipomannan$ Candida0albicans$ Mannan$ Candida0albicans$ Glucuronoxylomannan$ Cryptococcus0neoformans$ ' Parasites' tGPI)mutin$... of! cattle! whereas! M., mircoti, causes! disease! in! small! wild!mammals,!namely!voles,!wood!mice!and!shrews!(Brooks!et!al.,!2010;!Wells! and!Oxon,!1937).!!! Mycobacteria!cannot!be!classified !as! gram!positive!or!negative.!Instead,!they!are! characterised! as! acid.fast! bacteria! for! their! resistance! to! decolorisation! by! acid! alcohol! during! staining! procedures.! Mycobacteria! have! characteristic!... (TIRAP),! Toll/ IL1R! domain.containing! adaptor!inducing! IFNβ!(TRIF)!or!TRIF.related!adaptor!molecule!(TRAM)(Kawai! and!Akira,!2011).!! Two! main! TLR! signalling! pathways! have! been! characterised! to! date.! The! first! pathway,! common! to! all! TLRs,! is! through! MyD 88, ! leading! to! the! activation! of! nuclear! factor! kappa! B! (NFκB)! and! mitogen! activated! protein! kinase! (MAPK),! and!inflammatory!cytokine!production.!The!second,!only!described !for! TLR3!and!... Chapter!1:!Introduction! ! Mycobacterium- tuberculosis 1.1.1 Mycobacteria The! Mycobacterium, (M.)! genus! encompasses! several! pathogenic! species! that! have! exacted! an! alarming! toll! of! human! morbidity! and! mortality.! Mycobacteria! are! rod.shaped,! aerobic! bacteria! consisting! of! over! 125! species! that! are! medically!classified!into!three!groups!on!the!basis !of! their!pathology,!diagnosis! and! treatment!... Uptake.and.Recognition .of. Mycobacteria.by.Macrophages Mycobacteria! engage! multiple! surface! receptors! on! the! macrophage! and! are! taken!up!via !receptor. mediated!phagocytosis.!!Complement!receptors!mediate !a! major!route !of! mycobacteria!phagocytosis!via!complement!opsonisation !as! well! as! nonopsonic! entry! through! the! recognition! of! mycobacterial! surface! polysaccharides!(Cywes!et!al.,!1996;!Cywes!et!al.,!1997;!Schorey!et!al.,!1997). !A! ... The !innate! immune! system!is!the!first!line !of! defence!against!invading!pathogens,! and!is!based!on!the!recognition !of! molecular!signatures!that!are!broadly!shared! across!pathogens!and!thus!discriminate!against!self.cells!and!tissues.!!Detection! of! these! pathogen! associated! molecular! patterns! (PAMPs)! is! mediated! by! PRRs! that! initiate! a! host! defence! response! against! the! invading! pathogen!... PRRs!are!independent !of! immunological!memory!and!recognise!PAMPs!that!are! usually!essential !for! pathogen!survival,!and !as! such,!difficult!to!alter!(Akira!et!al.,! 2006).! PRRs! are! also! constitutively! expressed,! and! can! detect! pathogens! at! all! stages! of! their! life! cycle! (Akira! et! al.,! 2006).! Each! PRR! has! distinct! expression! patterns!in!varying!cells!and!tissues !as! well !as! differential!functions!in!terms !of! ... microbial! pathogens! are! composed! of! a! number! of! PAMPs,!and!therefore!potentially!activate !a! combination !of! PRRs.!TLRs!activate! signalling! pathways! tailored! to! pathogen.specific! immune! responses! by! recruiting! specific! combinations! of! TIR! domain! containing! adaptor! proteins! including! myeloid! differentiation! primary! response! gene! (88 )! (MyD 88) ,! TIR! domain! containing! adaptor!... caseation !of! the!centre!occuring !as! macrophages!die.!The!anaerobic!conditions,! as! well! as! low! pH! within! the! caseous! tissue! inhibit! the! growth! of! extracellular! MTB,! and! the! mycobacteria! may! remain! dormant! there! for! decades.! ! However,! under! conditions! of! failing! immune! surveillance,! disease! may! progress! via! the! liquefaction! of! the! caseous! center,! forming! an! air.filled! cavity! in!... Also,!individuals!with!chronic!granulomatous!disease, !a! genetic!disorder!wherein! mutations! in! the! NADPH! oxidase! complex! result! in! defectiveness! of! oxidative! defence! in! phagocytes,!are! vulnerable!to! mycobacterial!diseases! (Casanova! and! Abel,! 2002).! Mutations! in! natural! resistance! associated! macrophage! protein! 1! (Nramp1)! have! been! shown! in! mice! to! result! in! impaired! early! resistance! to! mycobacteria!infections,!in!particular!to!M.,bovis,BCG!(Gros!et!al.,!1 981 ;!Vidal!et! . ! ! "#$%$"&'%()$&(*+!*,!&* (/'!%'"'0&*%!1!$)!$!+'2! (++$&'!(3 3 4 +' !% '" '0 &* % !,*% !!"#$%&#'()*+!, '+%()#+-$.*.! ! ! ! *#!)''+!#4'5!*-(6($! 78) 9:!7#;<=:>?!+4)>! ! ! ! $!&#')()!) 483 (&&'@!! ,*%!&#'!@&apos ;A% ''!*,!@*"&*%!*,!0#(-*)*0#5. !!"#$%&#'()*+!, '+%()#+-$.*.! ! ! ! *#!)''+!#4'5!*-(6($! 78) 9:!7#;<=:>?!+4)>! ! ! ! $!&#')()!) 483 (&&'@!! ,*%!&#'!@&apos ;A% ''!*,!@*"&*%!*,!0#(-*)*0#5 ! ! ! @'0$%&3'+&!*,!3("% *8( *- *A5 ! ! ! +$&(*+$-!4+(6'%)(&5!*,!)( +A$ 0*%'! BCDB! ! ! ! $9E<;FGHIJHKH<L=! ! ! MM! !"#$%&'()*(+($,. =M<JGH!=LNO<IHI!NMU;<Q9GHM9!O9MI! &$'! ! ! &NM=.O9HLOLH.'@&$,! ! ! ! -M=L!;P!0QUGM9OLM;<=! ! ! [TM! & ;8! ! ! &QUHN9QG;=M=! & ;8) ! ! ! &NM=!UQPPHNHI!=OGM<H! & ;8) &! ! ! &NM=!UQPPHNHI!=OGM<H.LFHH<!! &(%!

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