Tus Hu Xov Tooj-Like Receptor Response To Hepatitis B Virus Infection and Potential Of TLR Agonists As Immunomodulators For Treating Hepatitis B Chronic Hepatitis B: Kev Saib Xyuas Ntu 2
Jun 21, 2023
3. Inhibition of Innate Immune Response los ntawm HBV Kab Mob
Cov txheej txheem tseeb ntawm kev tiv thaiv kab mob los yog inhibition los ntawm HBV tseem tsis meej. Ntxiv mus, seb HBV evades los yog inhibits innate lees paub, los yog txhawb kev tiv thaiv innate tseem tsis tau muaj pov thawj [75]. Txawm li cas los xij, HBV protein ntau, suav nrog HBsAg thiab HBeAg, cuam tshuam nrog HBV persistence, uas yog qhia txog lub luag haujlwm ntawm cov kab mob sib kis hauv kev tawm tsam ntawm lub cev tiv thaiv kab mob [76–78].
Kev tiv thaiv kab mob HBV yog hais txog lub peev xwm ntawm tus kab mob siab B kom hloov pauv lossis xaiv xaiv tus tswv lub cev tiv thaiv kab mob kom lub cev tiv thaiv tsis tuaj yeem tshem tawm tus kab mob zoo. Cov txheej txheem evasion no yog ib qho ntawm cov laj thawj tseem ceeb rau kev mob siab rau mus sij hawm ntev, rov ua dua, thiab rov ua dua ntawm HBV.
Kev tiv thaiv kab mob yog hais txog lub peev xwm ntawm tib neeg lub cev tiv thaiv kab mob tiv thaiv kab mob. Rau cov neeg muaj kab mob HBV, cov neeg muaj kev tiv thaiv kab mob muaj zog tuaj yeem tsim cov tshuaj tiv thaiv kab mob ntau hauv lawv lub cev, uas tuaj yeem txhawb kev tiv thaiv kab mob thiab pab tshem tawm tus kab mob; cov neeg uas tsis muaj zog tiv thaiv kab mob yuav muaj ntau yam kab mob siab B thiab muaj peev xwm hloov mus ua kab mob siab B.
Yog li ntawd, kev tiv thaiv kab mob HBV muaj feem cuam tshuam nrog kev tiv thaiv kab mob. Kev tiv thaiv muaj zog tuaj yeem kov yeej txoj kev khiav tawm ntawm tus kab mob, thaum kev tiv thaiv tsis muaj zog tuaj yeem raug siv los ntawm tus kab mob kom ua rau lub cev noj qab haus huv ntxiv. Yog li ntawd, kev txhim kho kev tiv thaiv kab mob yog ib qho tseem ceeb rau cov neeg mob kab mob siab B los txhim kho lawv txoj kev tiv thaiv kab mob. Los ntawm qhov kev xav no, peb yuav tsum txhim kho kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo. Cov polysaccharides hauv Cistanche tuaj yeem tswj hwm kev tiv thaiv kab mob ntawm tib neeg lub cev tiv thaiv kab mob, txhim kho kev ntxhov siab ntawm lub cev tiv thaiv kab mob, thiab txhim kho kev tiv thaiv kab mob hauv lub cev. Cov kab mob bactericidal.
Nyem qhov txiaj ntsig kev noj qab haus huv ntawm cistanche
Ntau qhov kev tshawb fawb tau txhim kho peb txoj kev nkag siab ntawm kev tiv thaiv kab mob hauv lub cev los ntawm HBV [38,79]. HBV tau raug tshaj tawm los txwv TLR-mediated antiviral teb nyob rau hauv cov kab mob siab los ntawm kev cuam tshuam nrog kev ua kom IRF-3, nuclear factor kappa B (NF-κB), thiab extracellular signal-regulated kinase (ERK) 1/2 [ 80] ib. HBV tau pom tias inhibit TLR9 cov lus teb los ntawm inhibiting MyD88-IRAK4 axis hauv pDCs tau los ntawm cov neeg mob [54]. Hauv lwm txoj kev tshawb fawb, TLR9 kev qhia thiab TLR9-kev ua haujlwm nruab nrab ntawm B cell tau raug tshem tawm hauv txhua qhov txuas B cell subsets raug rau HBV [81].
Kev tsis pom zoo ntawm TLR4, 8, thiab 9 nyob rau hauv peripheral DC subsets los ntawm cov neeg mob uas muaj tus kab mob HBV mob ntev kuj tau tshaj tawm [82], uas ua rau txo qis hauv lub cev tsis muaj zog. HBV polymerase tau tshaj tawm los thaiv kev ua kom IRF los ntawm kev cuam tshuam kev cuam tshuam ntawm IκB kinase-ε thiab DEAD-box RNA helicase thiab inhibiting IFN ntau lawm [83]. Lwm txoj kev tshawb fawb tau pom qhov inhibition ntawm STING-mediated IRF-3 ua kom thiab IFN- tsim los ntawm HBV polymerase [84]. HBsAg tau tshaj tawm los txwv kev ua kom NF-κB, IRF-3, thiab MAPKs hauv murine hepatocytes [85]. Ntxiv mus, T-cell activation induced los ntawm TLR3-stimulated murine KCs los yog LSECs kuj suppressed los ntawm HBsAg [85], qhia txog lub peev xwm ntawm HBsAg kom txo qis los yog inhibit TLR-mediated immune teb. Siv RPMI 8226, tib neeg myeloma B cell kab, nws tau pom tias HBsAg ua rau TLR9 tsis ua haujlwm los ntawm kev ua kom HBsAg-induced phosphorylation, uas ua kom muaj qhov hloov pauv, CREB, yog li tiv thaiv TLR9 txhawb kev ua haujlwm [81].
Ib txoj kev tshawb fawb tsis ntev los no kuj tau tshaj tawm HBsAg-kev cuam tshuam kev cuam tshuam ntawm NF-κB txoj hauv kev los ntawm kev cuam tshuam nrog TAK1 thiab TAB2, ua rau muaj kev tiv thaiv tiv thaiv kab mob [86]. Ntxiv mus, HBc-mediated downregulation ntawm interferon-induced transmembrane protein 1 (IFITM1) qhia [87] thiab HBeAg-mediated suppression ntawm NF-κB signaling pathway, inhibiting innate tiv thaiv teb [88,89], kuj tau tshaj tawm. HBV X protein (HBx) ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv lub cev tiv thaiv kab mob hauv lub cev, thiab ntau qhov kev tshawb fawb tau qhia txog kev koom tes ntawm HBx hauv kev tawm tsam ntawm hom I IFN ntau lawm los ntawm kev txo qis MAVS protein [90–93]. HBx-mediated downregulation ntawm TIR-domain-muaj adaptor-inducing interferon-beta (TRIF), ib feem tseem ceeb ntawm kev tiv thaiv kab mob hauv lub cev, kuj tau pom [43]. HBx tuaj yeem cuam tshuam qhov kev hloov pauv ntawm TRIM22 los ntawm ib qho CpG methylation hauv nws 5'-UTR, txo qhov kev sib txuas ntawm IRF-1 thiab inhibiting IFN-mediated anti-HBV teb [94]. Tsis ntev los no, cov txheej txheem tseem ceeb ntawm kev tiv thaiv kab mob hauv lub cev los ntawm HBx hauv hepatocytes tau tshaj tawm, qhov twg HBx-induced adenosine deaminases ua rau RNA 1 (ADAR1) deaminates adenosine los tsim inosine los ntawm kev cuam tshuam nrog HBV RNAs thiab zam kev tiv thaiv tus tswv tsev [19].
Kev tiv thaiv kab mob los ntawm kev txo qis RIG-I signaling ntawm N6 methyladenosine (m6A) hloov kho ntawm HBV RNAs tau tshaj tawm yav dhau los [95]. Tsis ntev los no, HBV-induced N6 m6A hloov kho ntawm phosphatase thiab tensin homolog (PTEN) cuam tshuam rau hauv lub cev tiv thaiv kab mob nrog txo IRF-3 dephosphorylation thiab IFN synthesis kuj tau tshaj tawm [96]. Zhou et al. tau tshaj tawm tias HBV inhibited RIG-I-induced IFN ntau lawm los ntawm kev tsim cov ternary complex nrog rau hexokinase thiab sequestering MAVS los ntawm RIG-I [97]. Kev puas tsuaj ntawm NK cell ua haujlwm los ntawm HBV kuj tau tshaj tawm [98]. HBV tuaj yeem khiav tawm cGAS qhov kev paub hauv HepG2-NTCP hlwb nrog rau txoj hauv kev ua haujlwm zoo cGAS-STING [99]; Txawm li cas los xij, lub tshuab tseem tsis paub. Tsis tas li ntawd, kev ua qauv qhia ntawm qhov hnov qab ntawm HBV rcDNA liab qab tab sis tsis yog HBV virions kis los ntawm cGAS hauv PHH qhia txog qhov tsis zoo ntawm cGAS hnov qab thaum kis HBV [99,100], txawm hais tias qhov tseeb mechanism tseem tsis meej.
Los ntawm cov kev tshawb pom saum toj no, nws yog qhov tsim nyog los txiav txim siab tias tsim kom muaj tus kab mob HBV thiab nws cov khoom siv protein tuaj yeem cuam tshuam / cuam tshuam tus tswv tsev hauv lub cev tiv thaiv kab mob (Daim duab 2) los ntawm cov txheej txheem paub thiab tsis paub, thiab yog li ntawd, kev nkag siab ntxaws txog kev tiv thaiv kab mob tiv thaiv kab mob / evasion. Nws yog ib qho tseem ceeb rau kev tsim kho tshiab thiab cov tswv yim tiv thaiv kom tswj tau tus kab mob HBV.
4. Muaj peev xwm ntawm TLR Agonists ua Immunomodulators
Raws li kev tiv thaiv kab mob tiv thaiv kab mob HBV mob ntev, kev kho cov kab mob tiv thaiv kab mob yog qhov tseem ceeb rau kev txhim kho cov kab mob ntev, uas tuaj yeem ua tiav siv cov tshuaj tiv thaiv kab mob, xws li TLR agonists, checkpoint inhibitors, thiab tshuaj tiv thaiv kab mob [4,101,102]. Hauv txoj kev tshawb no, peb tau tsom mus rau kev siv TLR agonists ua immunomodulators los txhim kho lub cev tiv thaiv kab mob hauv cov kab mob ntev. TLR agonists ua lub luag haujlwm tseem ceeb hauv kev hloov kho cov teebmeem immunotherapeutic [103,104]. Tsis ntev los no, TLR agonists tau txaus siab rau kev siv tshuaj tiv thaiv kab mob lossis tshuaj tiv thaiv kab mob vim tias lawv muaj peev xwm ua rau muaj kev tsim cov IFN, proinflammatory cytokines, thiab chemokines, uas yuav ua rau muaj kev cuam tshuam los tiv thaiv HBV [105,106]. TLR1/2 thiab TLR3 agonists tuaj yeem cuam tshuam HBV replication hauv PHH [105].
Lwm txoj kev tshawb fawb tau pom tias GS-9620 (vesatolimod), qhov ncauj TLR7 agonist, nrog rau nucleos(t)ide analogs (NAs) tau txhim kho cov tshuaj tiv thaiv kab mob los ntawm kev ua kom T cell thiab NK cell teb thiab txo lub peev xwm ntawm NK. cov hlwb txhawm rau txhawm rau T hlwb hauv cov neeg mob mob ntev [107]. Txawm li cas los xij, tsis muaj qhov hloov pauv tseem ceeb hauv qib HBsAg tau pom tom qab kev kho ua ke nrog NAs thiab GS-9620 [107]. Ib txoj kev tshawb fawb tsis ntev los no tau pom tias ob leeg ua yeeb yam TLR7/8 (R848) thiab TLR2/7 (CL413) agonists muaj zog ntau dua hauv inhibiting HBV replication dua li ib leeg ua yeeb yam TLR7 (CL264) lossis TLR9 (CpG-B) agonists [108], uas qhia txog qhov muaj peev xwm ntau dua ntawm kev ua yeeb yam TLR agonists hauv kev ua kom dav cytokine repertoires. Ntau qhov kev tshawb fawb tau pom tias muaj peev xwm ntawm TLR agonists los tua HBV hauv cov qauv tsiaj.
Hauv kev tshawb fawb yav dhau los, GS-9620 tau pom tias ua rau muaj kev tiv thaiv kab mob los ntawm kev tsim cov IFN-, lwm yam cytokines, thiab cov tshuaj chemokines hauv cov kab mob chimpanzees. Nws txo cov kab mob kis ntau dua 2 lub cav thiab cov ntshav HBsAg thiab HBeAg qib los ntawm 50 feem pua [109], qhia txog qhov ua tau zoo ntawm TLR7 agonists hauv kev kho mob HBV mob ntev thiab txhawb kev tshawb nrhiav ntxiv ntawm tus neeg sib tw no hauv tib neeg CHB. Hauv lwm txoj kev tshawb fawb tsis ntev los no, cov txheej txheem ntawm GS-9620 kev ua haujlwm tau tshawb xyuas hauv CHB chimpanzees, thiab nws tau tshaj tawm tias GS-9620 tawm tswv yim los tiv thaiv HBV cov lus teb cuam tshuam nrog kev sib sau ntawm lub cev tiv thaiv kab mob hauv daim siab uas tuaj yeem yog tua cov kab mob HBV lossis tuaj yeem tiv thaiv HBV los ntawm kev kis kab mob tshiab los ntawm kev tsim cov tshuaj tiv thaiv [110].
Hauv cov qauv woodchuck ntawm CHB, kev tswj hwm ntawm GS-9620 kuj tau ua rau txo qis hauv cov kab mob DNA thiab intrahepatic woodchuck kab mob siab (WHV) DNA replicate intermediates, WHV cccDNA thiab WHV RNA [111], qhia tias cov TLR7 agonist yog lub zog immunomodulator nrog cov teebmeem los tiv thaiv HBV hauv cov qauv ntoo. Ntxiv mus, qhov xwm txheej ntawm HCC tau txo qis hauv GS-9620- kho woodchucks [111]. Hauv lwm txoj kev tshawb fawb, nws tau pom tias kev tswj hwm qhov ncauj ntawm lwm tus TLR7 agonist, APR002, ua ke nrog entecavir (ETV) txhim kho ISG qhia thiab txo WHV cccDNA hauv cov ntoo chucks ntev nrog WHV [112]. Hauv theem 1b kev sim tshuaj, kev tswj hwm qhov ncauj ntawm GS-9620 tau pom tias muaj kev nyab xeeb thiab muaj kev tiv thaiv zoo, uas txhim kho peripheral ISG15 ntau lawm yam tsis muaj qhov tseem ceeb hauv IFN- theem [113]. AL-034, tus kws kho qhov ncauj TLR7 agonist, tau pom qhov ua tau zoo tiv thaiv HBV hauv tus qauv nas [114].
Kev ntsuam xyuas ntawm HBV cov tshuaj tiv thaiv kab mob uas muaj cov tshuaj tiv thaiv tshiab TLR7 agonist (lub npe T7-EA), alum adjuvant, thiab recombinant HBsAg protein, qhia tias T7-EA induced Th{{3} } hom tshuaj tiv thaiv kab mob, nrog rau cov lus teb T-cell ntxiv thiab HBsAg-specific IgG2a titer hauv tus qauv nas [115]. Ib txoj kev tshawb fawb yav dhau los tau tshaj tawm tias TLR8 agonist ssRNA40 tuaj yeem xaiv ua kom lub siab nyob hauv lub cev tiv thaiv kab mob, thiab mucosal-associated invariant T cells thiab NK hlwb raug txheeb xyuas tias yog IFN- - tsim cov hlwb tom qab TLR8 ua kom [116], uas qhia txog qhov ua tau zoo. ntawm kev siv TLR8 agonist hauv kev kho CHB. GS-9688 (selgantolimod), ib lub qhov ncauj TLR8 agonist, tau pom tias yog lub zog tiv thaiv HBV molecule hauv HBV-infected thawj tib neeg hepatocytes [117].
Hauv lwm txoj kev tshawb fawb, GS-9688 tau tshaj tawm kom siv cov tshuaj tiv thaiv HBV hauv woodchuck qauv ntawm CHB [118], qhov uas nws txo cov kab mob ntau tshaj 5 lub cav thiab suppressed woodchuck hepatitis nto antigen (WHsAg) hauv 50 feem pua. kho mob chronic woodchucks [118]. Lwm qhov kev tshawb fawb tsis ntev los no kuj tau qhia txog kev kho mob muaj peev xwm ntawm GS-9688 hauv CHB, qhov twg GS-9688 induced cytokines hauv tib neeg PBMCs uas tuaj yeem ua rau cov tshuaj tiv thaiv kab mob ua haujlwm los ntawm cov tshuaj tiv thaiv kab mob sib txawv, suav nrog NK hlwb, HBV-specific CD8 ntxiv. T hlwb, CD4 ntxiv rau follicular helper T cells, thiab mucosal-associated invariant T cells [119]. Kev ua haujlwm tiv thaiv HBV ntawm TLR9-ligand tau tshaj tawm yav dhau los [120,121]. Lub TLR9 agonist, CpG oligodeoxynucleotides (ODNs), kuj tau soj ntsuam hauv cov qauv ntoo, thiab nws tau pom tias qib WHsAg cov ntshav tau raug txwv los ntawm kev tswj hwm ntawm CpG thiab ETV, tab sis tsis muaj kev cuam tshuam nrog tus neeg sawv cev ib leeg [122] , qhia txog kev sib koom ua ke. CpG oligonucleotides nce HBV-specific IL2 thiab IFN- cov lus teb hauv cov ntshav tag nrho txhawb nqa nrog HBsAg lossis HBcAg [123]. Ib txoj kev tshawb fawb yav dhau los tau tshaj tawm txog lub peev xwm ntawm AIC649, TLR9 agonist, hauv kev txo qis WHV DNA, thiab WHsAg hauv ib qho piv txwv biphasic teb [124].
Tsis ntev los no, nws tau pom tias AIC649, ua ke nrog ETV, tuaj yeem tiv thaiv WHV DNA thiab WHsAg hauv woodchuck qauv ntawm CHB [125]. Ib txoj kev tshawb fawb yav dhau los tau qhia txog kev siv TLR3 ligand, poly (I: C), uas yog ib qho tshuaj tiv thaiv zoo rau HBV cov tshuaj tiv thaiv kab mob (npe hu ua pHBV-vaccine), uas muaj txiaj ntsig zoo tiv thaiv HBV replication [126]. Ib txoj kev tshawb fawb tsis ntev los no kuj tau tshaj tawm txog kev txhim kho ntawm daim siab kab mob thaum poly (I: C) tau xa los ntawm calcium phosphate nanoparticles conjugated nrog F4/80 antibody. Nws kuj tau txhim kho T-cell cov lus teb thiab tsim cov cytokines intrahepatic thiab chemokines, uas txo qis HBsAg, HBeAg, thiab HBV DNA qib hauv cov nas [127]. Ib txoj kev tshawb fawb tsis ntev los no tau pom tias HBV cuam tshuam nrog SIGLEC-3 (CD33) thiab tau ua lub chaw tiv thaiv kab mob tiv thaiv kab mob HBV thiab ua rau lub cev tsis muaj zog [128].
Hauv PBMCs los ntawm cov neeg mob CHB, nws kuj tau pom tias anti-SIGLEC-3 mAb tuaj yeem thim rov qab cov txiaj ntsig thiab ua rau cov lus teb cytokine rau TLR-7 agonist, GS-9620 [128]. TLR agonists ua cov tshuaj tiv thaiv kab mob tam sim no tab tom tshawb nrhiav rau cov tshuaj tiv thaiv tib neeg sib txawv, suav nrog cov tshuaj tiv thaiv HBV, thiab pom muaj kev vam meej hauv kev tshawb fawb tshuaj tiv thaiv [129,130]. Cov tshuaj tiv thaiv uas muaj cov TLR agonist tshwj xeeb tuaj yeem ua rau cov TLR tshwj xeeb thiab txhim kho kev siv tshuaj tiv thaiv yam tsis muaj kev koom tes ncaj qha rau kev tiv thaiv kab mob [131,132].
Hauv kev tshawb nrhiav tshuaj kho hluavtaws ntev peptide (SLP)-raws li tshuaj tiv thaiv los kho HBV ntev, nws tau pom tias TLR2-ligand conjugation ntawm tus qauv HBV-core SLP ua rau cov neeg mob ua haujlwm T cell teb ex vivo [133 ], tawm tswv yim tias TLR agonists kuj tseem tuaj yeem ua cov tshuaj tiv thaiv kab mob HBV. Ib txoj kev tshawb fawb tsis ntev los no kuj tau pom muaj peev xwm ntawm PRR ligands los txhawb kev tiv thaiv kab mob hauv lub cev rau HBV tswj [134]. Yog li ntawd, kev siv TLR agonists hauv HBV kev kho mob / tshuaj tiv thaiv zoo li kev cog lus thiab tuaj yeem yog ib qho cuab yeej zoo hauv kev tswj hwm tus kab mob HBV, uas yuav tsum tau tshawb xyuas ntxiv. Cov TLR agonists ua immunomodulators hauv kev loj hlob yog qhia hauv Table 1.
5. Cov lus xaus
Txawm hais tias muaj cov tshuaj tiv thaiv HBV uas muaj txiaj ntsig, kev kis tus kab mob HBV ntev tseem yog teeb meem kev noj qab haus huv thoob ntiaj teb. Cov kev tshawb fawb tsis ntev los no tau hais txog HBV uas yog tus kab mob cunning, uas tseem ua rau muaj lus nug txog kev nyiag khoom ntawm HBV thiab qhia txog lub peev xwm ntawm tus kab mob los cuam tshuam nrog lub cev tiv thaiv kab mob hauv lub cev thiab tsim kom muaj kab mob. Los ntawm cov ntaub ntawv muaj, nws tau xav tias tus kab mob HBV ntev ua rau muaj kev cuam tshuam ntawm tus tswv tsev hauv lub cev tiv thaiv kab mob, suav nrog kev tawm tsam ntawm TLR cov lus teb thiab cov cytokines qis.
Qhov kev cuam tshuam ntawm tus tswv tsev hauv lub cev tiv thaiv kab mob los ntawm kev siv TLR agonists tuaj yeem pab kom nkag siab zoo ntawm tus tswv tsev hauv lub cev tiv thaiv kab mob, tshwj xeeb yog kev sib cuam tshuam ntawm TLRs thiab cov kab mob kis. Yog li, txawm hais tias TLR agonists tau pom cov txiaj ntsig tau zoo hauv kev txhim kho lub cev tsis muaj zog tiv thaiv kab mob thaum lub sij hawm kis kab mob HBV, cov kev tshawb fawb ntxiv yuav tsum tau tshawb xyuas cov txheej txheem tom qab hloov kho lub cev tiv thaiv kab mob thiab rov qab tiv thaiv kab mob.
Tus sau kev koom tes:
Conceptualization, MEHK, MK thiab KT-K.; sau ntawv-kev npaj ua ntej, MEHK; sau-saib thiab kho, MEHK, MK thiab KT-K.; kev saib xyuas, KT-K. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:
Txoj kev tshawb fawb no tau txais kev txhawb nqa los ntawm cov nyiaj pab (kev txhim kho tshuaj tshiab network) los ntawm Nyiv Lub Chaw Haujlwm Saib Xyuas Kev Kho Mob thiab Kev Txhim Kho (AMED).
Institutional Review Board Statement:
Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo:
Tsis siv tau.
Kev lees paub:
Peb xav ua tsaug rau Takahiro Sanada thiab Sayeh Ezzikouri rau lawv txoj kev sib koom tes zoo.
Kev tsis sib haum xeeb ntawm kev txaus siab:
Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.
Cov ntaub ntawv
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