Yuav Ua Li Cas Kom Tau Nrog Lub Siab Innate Immunity? Ib Viruses' Tale
May 31, 2023
Abstract
Nyob rau hauv lawv qhov kev tshawb nrhiav uas tsis muaj qhov xaus rau kev nyob mus ib txhis hauv lawv tus tswv tsev, kab mob siab kab mob tau tsim ntau txoj hauv kev los tiv thaiv lub siab lub cev tiv thaiv kab mob. Qhov kev tshuaj xyuas no qhia txog qhov sib txawv thiab cov txheej txheem ua haujlwm los ntawm cov kab mob no rau (i) tsim nyob rau hauv daim siab (passive nkag los yog active evasion los ntawm kev tiv thaiv kab mob) thiab (ii) nquag inhibit lub innate tiv thaiv teb (xws li kev hloov pauv ntawm cov qauv kev lees paub receptor qhia thiab / los yog kev taw qhia txoj hauv kev, kev hloov kho ntawm interferon cov lus teb thiab kev hloov kho ntawm lub cev tiv thaiv kab mob suav lossis phenotype).
Interferon yog ib qho tseem ceeb ntawm kev tiv thaiv kab mob, uas tuaj yeem txhim kho lub cev tiv thaiv kab mob los ntawm kev ua kom muaj ntau lub cev tiv thaiv kab mob thiab cov molecules. Txawm li cas los xij, interferon tuaj yeem ua rau muaj kev cuam tshuam ntawm interferon, nrog rau lub cev kub, qaug zog, anorexia thiab lwm yam kev phiv.
Yog li ntawd, thaum siv interferon rau kev kho mob, nws yog ib qho tsim nyog yuav tsum tau ua tib zoo saib xyuas cov tshuaj kom zoo thiab lub sijhawm siv, ua kom nws cov nyhuv immunomodulatory thiab txo qhov tshwm sim ntawm qhov tshwm sim tsis zoo. Tsis tas li ntawd, los ntawm kev txhim kho kev tiv thaiv ntawm lub cev, qhov tshwm sim ntawm cov tshuaj tiv thaiv interferon tuaj yeem txo, kom cov nyhuv kho tau zoo dua. Yog li ntawd, rau cov neeg mob uas xav tau kev kho mob rau interferon, kev noj qab haus huv txoj kev ua neej xws li tswj kev noj zaub mov kom txaus, txhim kho lub cev tiv thaiv, thiab kev npaj lub neej thiab kev ua haujlwm ua lub luag haujlwm tseem ceeb hauv kev txhim kho kev tiv thaiv thiab txo cov kev tsis zoo. Los ntawm qhov kev xav no, peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho kev tiv thaiv zoo vim Cistanche tseem muaj cov tshuaj tiv thaiv kab mob thiab tiv thaiv qog noj ntshav, uas tuaj yeem ua kom lub cev tiv thaiv kab mob muaj peev xwm tiv thaiv thiab txhim kho lub cev tiv thaiv kab mob.
Nyem cistanche deserticola ntxiv
KEYWORDS
anti-inflammatory, kab mob siab, innate tiv thaiv, interferon, siab, MHC, NF-κB, pro-inflammatory, PRR.
1|Taw qhia
Lub siab raug mus tas li rau ntau yam kab mob (xws li kab mob, kab mob thiab kab mob cab) uas tuaj yeem kis tus tswv tsev los ntawm 4 txoj kev sib txawv, suav nrog (i) cov kua dej tsis huv, (ii) yoov tshaj cum tom, (iii) cov zaub mov tsis huv thiab (iv) aerosols. Qhov kev tshuaj xyuas no yuav tsom mus rau cov kab mob siab kab mob siab uas rov ua dua hauv daim siab. Cov kab mob thiab kab mob parasite ntawm daim siab tau tham txog lwm qhov.1,2
Cov kab mob hepatotropical kis mus txog kwv yees li 540 lab tus tib neeg / xyoo, ua rau kwv yees li 1.4 lab tus neeg tuag (WHO qhia) (Daim duab 1). Thaum lawv suav txog tsuas yog 65.7 feem pua ntawm tag nrho cov kab mob siab / xyoo, cov kab mob kis los ntawm cov kua dej tsis huv sawv cev rau 92 feem pua ntawm cov neeg tuag (WHO ceeb toom). Thaum cov kab mob tau tsim, kab mob siab B (HBV), C (HCV) thiab Delta (HDV) cov kab mob tuaj yeem ua rau mob siab mob siab (AH), fibrosis, cirrhosis thiab/los yog kab mob siab hepatocellular (HCC). nws tus kab mob satellite, HDV, muaj.
Txawm li cas los xij, cov neeg mob uas tsis tau txhaj tshuaj tseem raug kev txom nyem los ntawm kab mob siab B (CHB) lossis kab mob siab B ntxiv rau D (CHBD) thiab yog li yuav tsum tau kho tas mus li nrog nucleos(t)ide analogues (NA), thiab / lossis episodically nrog pegylated-interferon alpha ( peg-IFN , 1 xyoo lossis 2 xyoo nyob rau hauv lub sijhawm), lossis kev sib xyaw ua ke; Txawm li cas los xij, cov kev kho mob no ua rau muaj kev ua haujlwm zoo hauv<10% of patients, highlighting the need for the development of new therapeutic approaches.3 Co-infection with HDV, diagnosed in around 5% of CHB patients,3,4 accelerates the pathogenesis with a low response rate to peg-IFNα. Importantly, Bulevirtide, a viral entry inhibitor, has recently received a conditional authorisation to treat HDV-infected patients (under the name Hepcludex or Myrcludex B). Regarding HCV, new direct anti-viral agents (DAAs) can cure the infection in chronically infected patients.3 The human cytomegalovirus (HCMV) can also infect the liver but only as a secondary site and therefore will not be further discussed in this review.
Ob tug kab mob no kis tau mus rau lub siab los ntawm enteric contamination (Daim duab 1): kab mob siab A (HAV) thiab kab mob siab E (HEV). Lawv sawv cev 24.9 feem pua ntawm tag nrho cov kab mob siab thiab 4 feem pua ntawm cov neeg tuag (WHO). Cov kab mob HAV thiab HEV tuaj yeem tiv thaiv tau los ntawm cov tshuaj tiv thaiv thiab tej zaum yuav ua rau AH. HEV kuj tau tshaj tawm tias ua rau muaj kab mob ntev hauv cov neeg mob tiv thaiv kab mob.5
Thaum kawg, 4 tus kab mob hepatotropic kis rau lawv tus tswv ntawm yoov tshaj cum tom (Daim duab 1), uas yog tus kab mob Dengue (DENV), virus West Nile (WNV), Yellow Fever virus (YFV) thiab Zika virus (ZIKV). Lawv sawv cev rau 9.3 feem pua ntawm cov kab mob siab, feem ntau yog vim DENV thiab 4 feem pua ntawm cov neeg tuag. Txawm li cas los xij, vim tias tsis muaj cov ntaub ntawv hais txog qhov cuam tshuam ntawm 4 tus kab mob no ntawm lub cev tiv thaiv kab mob hauv lub cev, tsuas yog kab mob siab kab mob siab (xws li HAV, HBV, HCV, HDV thiab HEV) yuav tau tham ntxiv hauv qhov kev tshuaj xyuas no.
Qhov tseem ceeb, lub siab, uas raug rau siab ntau ntawm cov khoom noj uas tau txais cov antigens, tau piav qhia tias yog tolerogenic.6 Txawm li cas los xij, feem ntau pom tias yog cov kab mob lymphoid thib ob, txhua lub hlwb tau nruab kom paub txog thiab ceeb toom tus tswv ntawm cov kab mob nkag mus.7 Qhov no dichotomy feem ntau yog vim muaj qhov siab ntawm qhov kev txhawb siab uas lub siab lub hlwb yuav tsum tau ua haujlwm piv nrog rau lwm yam kabmob.8 Yog li ntawd, nws sawv cev rau lub vaj tse zoo meej rau cov kab mob muaj peev xwm zam kom tsis txhob muaj kev lees paub thiab / lossis qhov kev kis mob tshwm sim nrog kev tiv thaiv tsis zoo.
Lub siab noj qab nyob zoo yog tsim los ntawm (i) parenchymal hlwb, lub hepatocytes (70 feem pua ntawm daim siab hlwb; koom nrog lub siab tiv thaiv kab mob), (ii) peb lub siab tshwj xeeb tsis yog parenchymal hlwb (NPCs): Lub Siab Sinusoidal Endothelial Cells (LSECs) ) (20 feem pua ; tsim cov phab ntsa sinusoidal), cov kab mob siab ntsws (HSCs) (5 feem pua -8 feem pua thaum quiescent; daim siab fibroblasts) thiab Kupffer hlwb (KCs) (4 feem pua ; nyob hauv macrophages) thiab (iii) daim siab-unspecific NPCs, pom nyob rau hauv cov hlab ntsha (monocytes) thiab / los yog infiltrating lub siab: Dendritic hlwb (DCs) thiab lymphocytes.9 Hais txog lub tom kawg, ib co subsets qhia innate functions, xws li lub ntuj Killer T (NKT) hlwb thiab Mucosal. -associated invariant T (MAIT) cov hlwb uas tau nruab nrog antigen paub txog kev muaj peev xwm.10 MAIT hlwb tuaj yeem ua haujlwm los ntawm cytokines thaum kis tus kab mob.11 Ntxiv mus, innate lymphoid cells (ILCs), txawm tias tsis muaj cov tshuaj tiv thaiv tshwj xeeb, tuaj yeem kho lub cev tiv thaiv kab mob thiab tswj cov ntaub so ntswg homeostasis thiab o. Natural Killer cells thiab type 1 innate lymphoid cells yog ILCs ntau tshaj plaws hauv daim siab.10
Lub cev tiv thaiv kab mob hauv lub cev paub txog ntau yam ntawm PathogenAssociated Molecular Patterns (PAMPs) nrog rau DangerAssociated Molecular Patterns (DAMPs; muaj feem xyuam rau dysregulation ntawm cellular functions). Cov motifs khaws cia no tau lees paub los ntawm Pattern Recognition Receptors (PRRs), ntawm cov neeg hu xov tooj zoo li receptors (TLR) yog tsev neeg loj tshaj plaws.12 Ntau PRRs tau nthuav tawm los ntawm lub siab nyob hauv cov hlwb, tso cai rau qhov dav dav.7,13 PRR ua kom muaj txiaj ntsig hauv ib qho Kev sim tam sim los tswj cov kab mob loj hlob lossis rov ua dua tshiab, ua raws li kev nthuav qhia ntawm Major Histocompatibility Complex II (MHC-II) molecule kom koom nrog cov lus teb tshwj xeeb.14 Tag nrho, xws li kev hnov mob ua rau ua kom muaj ntau yam kev tiv thaiv kab mob hauv qab (nuclear factor- kappa B [NF-κB], Akt, JAK-STAT los yog interferon regulatory factor [IRF] pathways), uas, nyob rau hauv lem, ua rau zus tau tej cov effectors (cytokines los yog IFN) lub luag hauj lwm rau qhov tsim nyog orchestration ntawm lub cev tiv thaiv teb. {9}} Cov tshuaj tiv thaiv kab mob no tuaj yeem txhawb nqa txoj hauv kev hauv autocrine thiab / lossis paracrine yam, yog li ua kom muaj kev ua haujlwm ntawm ob leeg kws tshaj lij thiab tsis muaj kev tshaj lij.
Yog li, txhawm rau tsim thiab tswj kev kis kab mob hauv lub siab, kev khiav tawm ntawm cov txheej txheem no yog xav tau los ntawm cov kab mob.
2|YUAV UA LI CAS YUAV UA LI CAS RAU HAUV LUB HLOOV: A VIRUS' PERSPECTIVE
2.1|Lub tswv yim Trojan nees
Xws li cov neeg Greek thaum ub, 2 kab mob siab kab mob tau tsim txhais tau tias nkag mus rau hauv cov hlwb yam tsis raug kuaj pom, yog li tshem tawm / ncua kev ua kom lub cev tiv thaiv kab mob. Txhawm rau tsim kom muaj kab mob, cov teeb meem sib txawv yuav tshwm sim (i) nkag mus rau lub siab, (ii) nkag mus rau cov hlwb tso cai los ntawm cov ntshav ncig thiab (iii) nkag mus rau hauv cov hlwb.
Cov kab mob feem ntau nkag mus rau lub siab los ntawm cov ntshav ncig. Yog li, nkag mus rau parenchymal hlwb los ntawm sinusoid, uas yog hla lub endothelium tsim los ntawm LSECs, feem ntau yog thawj qhov teeb meem ntsib. LSECs tau nruab nrog tshwj xeeb fenestration tso cai rau cov as-ham, thiab feem ntau cov kab mob, kom dhau mus. Nws tsim nyog hais tias raws li cov kab mob tshwj xeeb hauv siab xws li fibrosis, fenestrae tau ploj, uas tuaj yeem tiv thaiv ntau tus kab mob los ntawm kev nkag mus rau cov hlwb tso cai.18 Yog li ntawd, cov kab mob no yuav xav tau 'plawv B' los xyuas kom muaj cov kab mob muaj zog. Duck-HBV thiab HCV, yog li ntawd, siv transcytosis los ntawm LSECs thiab KCs. Thaum Duck-HBV zoo li tau khawb los ntawm LSECs nyob rau hauv ib qho tsis tshwj xeeb, 19 HCV siv lub receptor-mediated mechanism.
Tseeb tiag, HCV-E2 cuam tshuam nrog DC-tshwj xeeb intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) thiab daim siab/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) ntawm KCs thiab LSECs feem. ). Ntawm qhov kev ceeb toom, HIV-gp120 (Human Immunodeficiency Virus; uas txawm tias tsis yog kab mob siab tshwj xeeb, tau raug pov thawj tias kis mob rau lub siab hauv vitro thiab hauv vivo) kuj tau pom tias cuam tshuam nrog DC-SIGN. Txawm li cas los xij, nws tseem tsis tau paub yog tias qhov kev cuam tshuam no cuam tshuam rau tus kab mob transcytosis hauv LSECs thiab / lossis KCs, thiab qhov cuam tshuam hauv vivo ntawm cov txheej txheem no tseem tsis tau meej. Tus kab mob los ntawm kev paub los ntawm intracellular PRRs, uas yog ib qho kev mob tshwm sim pab cov kab mob kom tsis txhob muaj kev tiv thaiv kab mob.
Thaum kawg, thaum nws tau mus txog hepatocytes, HCV siv lub koom haum ntawm nws lub hnab ntawv cov proteins nrog high-/low-low-density lipoproteins (HDLs/VLDLs/LDLs) los txhim kho receptor-mediated cellular nkag los yog nkag los ntawm daim nyias nyias fusion. 25
Yog li, HBV thiab HCV muaj peev xwm zais los ntawm lub cev tiv thaiv kab mob nrog rau kev siv cov khoom noj muaj txiaj ntsig, ntawm lawv cov kev ua haujlwm zoo rau hauv cov hlwb tso cai.
2.2|Catch kuv yog tias koj tuaj yeem: yuav ua li cas cov kab mob siab ua kom dim kev lees paub
2.2.1|Extracellular khiav tawm: ntxiv txoj kev thiab pathogenic evasion
Txoj kev ntxiv ua rau muaj txiaj ntsig zoo ntawm cov kab mob sib kis uas ua rau tsim cov cytokines inflammatory, recruitment ntawm phagocytes thiab lysis ntawm cov kab mob pom; cov txheej txheem uas cov kab mob yuav tsum tau zam kom lawv cov kab mob kis tau zoo thiab sib kis.26
Kev khiav tawm los ntawm kev paub txog cov tshuaj tiv thaiv kab mob sib xyaw ua ke tuaj yeem ua tiav los ntawm ntau lub tswv yim: (i) txheej txheej ntawm cov kab mob los ntawm tus tswv tsev cov proteins, (ii) tsim cov quasi-hom los ntawm kev hloov thiab (iii) kab mob lwj. HCV tau raug qhia kom zam kom tsis txhob muaj cov tshuaj tiv thaiv kab mob los ntawm kev koom tes ntawm lub hnab ntawv cov protein nrog cov lipoproteins thiab glycans.25 Ib yam li ntawd, HAV thiab HEV raug tso tawm hauv daim ntawv quasi-enveloped (eHAV thiab eHEV raws li) uas zais cov hyper-immunogenic capsid / core Cheebtsam hauv Ib tug tswv tsev-membrane cloak.27 Lwm qhov tseem ceeb ntawm tus tswv tsev nquag nrhiav rau cov kab mob ntawm HCV yog CD59 (membrane inhibitor of reactive lysis). Yog li ntawd, qhov tsim ntawm qhov sib txuas-mediated membrane nres complex.30 Cov ntaub ntawv pov thawj los ntawm cov neeg mob kuj qhia txog kev sib koom ua ke ntawm CD59 rau hauv HCV-virions28 (Daim duab 2, point #1). Thaum kawg, HCV thiab HBV siv tus tswv tsev exosomes los kaw lawv cov txheej txheem cov protein thiab cov khoom siv caj ces (DNA thiab RNA) raws li pom hauv cov neeg mob.31,32 Cov hlwv no muaj qhov tshwj xeeb vaj tse raws li lawv muaj cov cellular membrane - yog li tshwm sim li tus kheej - thiab ntxiv rau. pab txhawb cellular nkag los ntawm fusion ntawm exosome nrog cell membrane. Cov txheej txheem no kuj tau pom nyob rau hauv lwm yam kab mob (xws li kab mob, fungal, parasitic), qhia txog ib tug redundant mechanism siv los ntawm cov kab mob kom tsis txhob muaj kev tiv thaiv kab mob thiab yooj yim mus cuag thiab kis tau lub hom phiaj.
Raws li lub tshuab thib ob ntawm kev khiav tawm ntxiv, HCV - tab sis kuj muaj lwm cov kab mob RNA los ntawm tsev neeg Flaviviridae (DENV, ZIKV, YFV thiab WNV) - thiab HDV xaiv cov kev hloov pauv tshwm sim hauv cov phiaj xwm feem ntau, feem ntau ntawm cov proteins, yog li cuam tshuam cov epitope paub thiab tom qab. Kev nthuav qhia antigen los ntawm MHC molecules. Lub tswv yim no tsim kom muaj qhov xav tau tsis tu ncua rau cov tshuaj tiv thaiv kab mob epitope tshwj xeeb hauv cov neeg mob.33,34 Txog rau qhov kawg no, ua ib feem tseem ceeb ntawm cov qauv epitope, muaj pes tsawg leeg thiab thaj chaw ntawm glycans txuas nrog cov kab mob hauv lub hnab ntawv cov protein, xws li HCV-E2, kuj tuaj yeem ua tau. be modulated.35 Kev tsim ntawm quasi-species, ntxiv rau kev cuam tshuam cov kab mob tshem tawm los ntawm txoj kev ntxiv, kuj yog ib qho teeb meem loj hauv kev tsim cov tshuaj tiv thaiv zoo tiv thaiv kab mob nrog kev hloov pauv sai sai.
Thaum kawg, thaum kis tus kab mob HBV, cov kab mob tsis kis kab mob (tsuas yog muaj HBV-HBsAg embedded nyob rau hauv cov lipid membrane) yog secreted ntau tshaj ({2}} ntau tshaj li kis kab mob). raws li ib tug decoy tiv thaiv lub cev tiv thaiv kab mob thiab yog li tso cai rau cov kab mob sib kis nrog tib txheej txheej (HBV-HBsAg) mus nkaum nyob rau hauv qhov muag pom. Yog li ntawd, nkag mus inhibitors lossis HBV-tshwj xeeb cov tshuaj tiv thaiv kab mob kho cov kab mob tshem tawm yuav tsum tau muab xa mus rau hauv qhov txaus txaus ntawm cov molecules los tiv thaiv cov kab mob thiab cov kab mob subviral particle.
Ua ke, cov tswv yim sib txawv no ua rau HAV, HBV, HCV (nrog rau lwm cov kab mob flaviviruses) thiab HEV kom dim ntawm cov tshuaj tiv thaiv kab mob- thiab ntxiv kev tuag.
2.2.2|Peek-a-Boo: intracellular zais ntawm cov kab mob
Thaum lawv tau nkag mus rau cov hlwb tso cai, cov kab mob yuav tsum zam kom tsis txhob muaj kev tiv thaiv kab mob hauv lub cev los ntawm PRRs.
Rau lub hom phiaj ntawd, HBV tsim ib daim ntawv zoo li tus tswv tsev / lub xeev ua rau muaj tus kab mob nyob hauv lub siab thiab muaj peev xwm rov ua tau tus kab mob. HBV genome nteg nyob rau hauv lub nucleus ntawm cov kab mob uas muaj kab mob raws li ib tug chromosome zoo li cov qauv, lub cccDNA (covalently kaw ncig DNA), yog li tsis tsim PAMPs. Yog li, txawm tias qee qhov kev sim tshwj xeeb, cytosolic PRRs tuaj yeem paub txog HBV genome, 37 tsuas yog ncua sijhawm thiab tsis muaj zog lossis tsis muaj lub cev tiv thaiv kab mob hauv lub cev raug kuaj pom hauv hepatocytes tom qab HBV kab mob. HBV los ntawm PRR recognition.40 Raws li qhov tshwm sim, cov tshuaj destabilizing HBV nucleocapsid tuaj yeem rov kho lub cev tiv thaiv kab mob los ntawm DNA sensors thiab tau pom cov txiaj ntsig zoo hauv vivo thiab hauv vitro.41
HCV tseem tuaj yeem tshem tawm cytosolic kev lees paub thiab ua kom muaj kev sib koom ua ke hauv cheeb tsam ntawm cov txheej txheem rov ua dua tshiab los ntawm kev hloov kho cov ntaub so ntswg thiab tsim cov khoom tshiab (piv txwv li ob-membrane vesicles ntawm 150 nm txoj kab uas hla).
Ua ke, cov tswv yim no txo qis PAMPs muaj rau kev lees paub.
3|LIVER VIRUSES STRIKE BACK: ACTIVE INHIBITION INNATE Immune SensING
3.1|Targeting professional immune sensors
3.1.1|PRRs
PRR sensing thiab activation induce NF-κB thiab IFN txoj hauv kev (sib tham hauv Tshooj 3b), uas yog qhov tseem ceeb los pib kev tshem tawm cov kab mob. Yog li, cov kab mob tau hloov kho cov tswv yim los ua kom PRR kev qhia / kev ua si.
TLR9, TLR3 thiab TLR2 kev qhia yog downregulated hauv PBMCs, daim siab macrophages thiab/los yog hepatocytes los ntawm cov neeg mob HBV-HBeAg ntev43-45 (Daim duab 2, point #2). Tsis tas li, HBV-HBsAg protein, los ntawm kev khi rau CD14 (TLR4 co-receptor), tuaj yeem txo TLR4 signaling ob leeg hauv vitro thiab hauv vivo46,47 (Daim duab 2, taw tes # 2). Txawm li cas los xij, TLR downregulation tsis tuaj yeem rov hais dua ex vivo thaum siv cov tshuaj tiv thaiv kab mob muaj zog, tawm tswv yim tias inhibition los ntawm HBV tuaj yeem kov yeej saum toj ib qho kev ua kom pib.48,49 Txawm hais tias tsis tau lees paub hauv tsev kho mob, HCV-NS3/4 lub hom phiaj Riplet, qhov tseem ceeb rau kev ua kom muaj zog ntawm intracellular PRR, RIG-I 50 (Daim duab 2, point #3).
Yog li, ntawm cov kab mob kab mob siab, HBV, tib tus kab mob uas tsis ua rau lub cev tiv thaiv kab mob thaum kis tus kab mob thawj zaug, kuj yog tib tus kab mob uas tau hloov zuj zus mus rau qhov muaj txiaj ntsig inhibition ntawm PRR qhia thiab / lossis kev ua haujlwm.
3.1.2|Targeting MHC kev nthuav qhia
Kev paub txog cov kab mob ua tau zoo ua rau muaj kev thauj khoom ntawm intracellular- lossis extracellular-derived peptides mus rau MHC-I lossis MHC-II molecules, feem. Lub siab yog tib lub cev uas qhov kev nthuav qhia tsis cuam tshuam los ntawm endothelial barrier, tso cai rau CD8 ntxiv rau T cell activation.51
CD8 ntxiv rau T cell qaug zog (piv txwv li txo CD8 ntxiv rau T cell muaj nuj nqi) yog ib qho cim ntawm CHB cov neeg mob. Tsis ntev los no, qhov txheej txheem no yog, tsawg kawg yog ib feem, vim yog tsis txaus priming ntawm hepatocytes lossis LSEC. Qhov no qhia txog qhov sib txawv ntawm kev hloov pauv thiab kev ua haujlwm ntawm MHC kev nthuav qhia hauv daim siab hlwb thaum kis HBV. Txawm li cas los xij, cov txheej txheem tshwj xeeb tseem yuav raug tshem tawm. Hauv HBV-HDV cov neeg mob sib koom ua ke, HDV, los ntawm inducing txoj kev IFN, boosts HBV kev nthuav qhia.55 Txawm tias tsis txaus rau thim rov qab CD8 ntxiv rau T cell, txawm li cas los xij, nws tseem muaj txiaj ntsig zoo rau kev tshem tawm HBV thaum lub sij hawm kho T cell, tseem ceeb. qhov tseem ceeb ntawm kev tsim cov tshuaj tiv thaiv kab mob tshiab los ua kom lub cev tiv thaiv kab mob hauv lub cev. Ntawm qhov tod tes, MHC-I kev nthuav qhia yog attenuated nyob rau hauv HCV-mob hlwb kho nrog IFN, ua rau txo CD8 ntxiv rau T cell effector functions56 (Daim duab 2, point #4).
Ua ke, HBV thiab HCV tuaj yeem hla qhov kev ua kom lub cev tiv thaiv kab mob los ntawm (i) txo qis hauv kev lees paub thiab (ii) tau txais txiaj ntsig los ntawm ib puag ncig tolerogenic lossis hloov kho MHC-kev nthuav qhia.
3.2|Modulating intracellular innate kev tiv thaiv kab mob
3.2.1|PRRs 's downstream signaling pathways
Raws li twb tau hais lawm, kev ua kom PRRs ua rau 2 txoj hauv kev tseem ceeb: IRF thiab NF-κB. Lawv induction yog tswj los ntawm qhov tseem ceeb adapter molecules, uas yog mitochondrial anti-viral signaling protein (MAVS; RNA sensing), STING (DNA sensing) thiab MyD88 los yog TIR domain-muaj adapter inducing IFN (TRIF; feem ntau TLR signaling).
Raws li tus kab mob RNA lees paub los ntawm RIG-I lossis MDA5, MAVS tau qhib ua haujlwm ua rau muaj kev cuam tshuam ntawm NF-κB signaling thiab proinflammatory cytokine secretion. Txawm li cas los xij, MAVS yog qhov tsis zoo hauv nws txoj haujlwm los ntawm HAV, HCV thiab HBV, 57,58 ua rau lub cev tsis muaj zog (Daim duab 2, point #5i-5ii). Qhov kev puas tsuaj no ua tiav los ntawm MAVS cleavage lossis degradation, kho los ntawm (i) HCVNS3/4A (serine protease), (ii) HAV-3ABC (cysteine protease) 57,59,60 thiab (iii) HBV-HBx ( los ntawm Lys136 ubiquitination).58 Ntawm kev ceeb toom, tshwj tsis yog rau HCV, uas qhov kev sib cais los ntawm virion-encoded proteases kuj tau pom hauv vivo, feem ntau ntawm cov kev tshawb fawb no tsuas yog ua hauv vitro ( kis kab mob lossis overexpression ntawm cov kab mob kis kab mob). Qhov phenotype no tuaj yeem, txawm li cas los xij, piav qhia txog qhov txo qis pro-inflammatory cytokines pom hauv cov neeg mob.
STING, lub cytosolic DNA sensor, cuam tshuam ntawm nws tus kheej nrog ob qho tib si MAVS thiab TBK1 (ib qho protein nyob rau ntawm txoj kev sib tshuam ntawm NF-κB thiab IRF signaling), ua rau kev ua kom NF-κB thiab IRF3/7 thiab tom qab IFN thiab cytokine ntau lawm. Qhov kev sib cuam tshuam ntawm STING nrog TBK1 yog inhibited los ntawm HCV-NS4B61 (Daim duab 2, cov ntsiab lus #6-7). Ib yam li ntawd, kev sib cuam tshuam ntawm TBK1 / IKKε thiab DEAD lub thawv RNA helicase (DDX3; implicated nyob rau hauv induction ntawm IFN-I) yog abrogated los ntawm HBVpol62 (Daim duab 2, point #8) thiab cov txheej txheem deubiquitination, yuav tsum tau rau RIG-I/TBK1 Kev ua kom muaj zog, txo qis los ntawm HEV-ORF1 papain-zoo li cysteine protease (PCP) domains (Daim duab 2, point #9).63 Tom qab ntawd, kev ua kom qis qis IRF3/7 raug tiv thaiv. Tsis tas li ntawd, IRF3/7 raug txwv ncaj qha hauv vitro los ntawm kev thaiv ntawm poly(I: C)-mediated IRF3 phosphorylation lossis degradation ntawm IRF7 mRNA raws li kev siv los ntawm HEV-ORF1 X domain thiab HBV-HBsAg, raws li (Daim duab 2, point # 10). 63,64 ib
Hauv vitro, TLR3 thiab TLR4 teeb liab tuaj yeem cuam tshuam los ntawm kev hloov kho qhov qhia ntawm lawv cov adapter molecule TRIF. TRIF yog cleaved thiab degraded ncaj qha los yog los ntawm caspase activation los ntawm HCVNS3/4A, HCV-NS4B thiab HAV-3CD viral proteases65,66 (Daim duab 2, point#11). Tsis tas li ntawd, HBV thiab HCV tuaj yeem cuam tshuam MyD88- nyob ntawm TLR signaling (piv txwv li feem ntau ntawm lwm cov tswv cuab ntawm TLR tsev neeg) los ntawm kev sib cais los yog degradation ntawm cov teeb liab molecules TRAM thiab TRAF6, yog li tiv thaiv kev tiv thaiv kab mob 67,68 (Daim duab 2. , point#12-13).
Ntxiv mus, NF-κB txoj kev taw qhia lub cev muaj zog yog tsom rau ntau lub siab kab mob. Whereas 2 NF-κB txoj kev taw qhia tau piav qhia (piv txwv li txoj kev canonical induced los ntawm NEMO thiab txoj kev tsis-canonical ntxias los ntawm NIK), tsuas yog txoj kev canonical yog tsom los ntawm kab mob siab. Ib lub hom phiaj tseem ceeb hauv qhov cascade yog IKK complex, tsim los ntawm NEMO (tseem hu ua IKKy), IKK thiab IKK . Lub koom haum ntawm linear ubiquitin chain assembly complex (LUBAC) nrog NEMO yog qhov tseem ceeb rau nws txoj kev ua kom tsim nyog, cov txheej txheem uas yog precluded los ntawm kev sib tw binding ntawm HCV-NS3 rau LUBAC69 (Daim duab 2, point # 14i). Tsis tas li ntawd, IKK complex tuaj yeem degraded los ntawm NEMO cleavage los ntawm HAV-3C ntawm Q304 residue70 (Daim duab 2, point #14ii). Ntxiv mus, cov canonical txoj kev taw qhia los ntawm IκB complex, muaj xws li IκB thiab IκB . Lub ubiquitin-mediated chaw nyob ntawm IκB complex rau cov proteasome los ntawm E3 ubiquitin ligase TRCP tso tawm NF-κB complex, ua rau nws translocation rau hauv lub nucleus. Cov txheej txheem no tiv thaiv los ntawm kev khi ntawm HEV-pORF2 rau E3 ubiquitin ligase TRCP71,72 (Daim duab 2, point #15). Thaum kawg, kev hloov pauv ntawm ntau lub NF-κB subunits, tshwj xeeb tshaj yog RelA (los yog p65), mus rau lub nucleus yog inhibited los ntawm HCV-core thiab HCV-polyprotein, uas tau pom nyob rau hauv tib neeg DCs73 (Daim duab 2, point # 16).
Ua ke, inhibition ntawm sensors (MAVS thiab STING), adapter molecules (TRIF thiab MyD88), los yog NF-κB txoj kev, qhia txog qhov ua kom zoo tshaj plaws ntawm kev tiv thaiv kab mob thaum kis kab mob siab. Txawm hais tias kev lees paub hauv cov neeg mob ploj lawm, cov txheej txheem inhibitory ntawm NF-κB thiab IRF cov kev taw qhia tuaj yeem ua rau muaj kev txo qis ntawm cov neeg kho mob inflammatory pom hauv cov neeg mob.
3.2.2|IFN receptor downstream signaling
IFN-I (IFN thiab IFN) thiab IFN-II (IFN) khi rau lawv cov receptors, IFNAR thiab IFNGR, thiab qhib cov teeb liab qis. Tom qab ntawd, interferon-stimulated genes (ISGs) raug ntxias, txhawb kev tiv thaiv kab mob. Nws yog ib qho tsim nyog sau cia tias ib sab ntawm cov txheej txheem inhibitory tau piav qhia, qee cov kab mob ua rau IFN ntau lawm los ntawm PRR paub txog lawv cov nucleic acids, xws li HCV nrhiav tau los ntawm RIG-I thiab HDV nrhiav los ntawm MDA-5. Txawm li cas los xij, qee cov pov thawj qhia txog kev cuam tshuam nrog IFN txoj hauv kev, uas tuaj yeem ua rau lub cev tsis muaj zog ntxiv txawm tias tom qab paub txog cov kab mob ua tiav.
Ua ntej, hauv cov kab mob hepatoma, kev qhia ntawm IFNAR lossis nws qhov kev ua kom thiab kev taw qhia los ntawm lub adapter molecule Tyk2 yog precluded los ntawm HCV thiab HDV, raws li 74,75 (Daim duab 2, cov ntsiab lus #17-18). Ntxiv mus, cov kev ua ntawm cov ntsiab lus transcription STAT1/2 (cim transducer thiab activator ntawm transcription) yog tiv thaiv los ntawm HBV-Pol thiab HDV proteins los ntawm impairing nws phosphorylation thiab/los yog nuclear translocation nyob rau hauv vitro74,76 (Daim duab 2, point #19) . HBV-mediated inhibition ntawm STAT1/2 nuclear translocation tau lees paub hauv CHB cov neeg mob lub siab biopsies. Txawm hais tias kev tshawb fawb hauv HDV cov neeg mob tsis muaj, qhov kev pom zoo inhibition tuaj yeem suav nrog qhov ua tau zoo ntawm IFN kev kho mob hauv cov neeg mob HDV.76.
Tsis tas li ntawd, qee cov pov thawj taw qhia rau kev ncaj qha inhibition ntawm ISG qhia, ua rau txo qis ntawm cov tshuaj tiv thaiv kab mob tseem ceeb, xws li myxovirus resistance A (MxA), tsuas yog pom hauv HBV-transfected Huh7, thiab tripartite motif 22 (TRIM22) protein. , raws li pom nyob rau hauv thawj tib neeg hepatocytes thiab daim siab biopsies77,78 (Daim duab 2, point #20). Qhov kev txwv ob npaug no (piv txwv li ntawm qhov taw qhia thiab cov lus qhia effector) tuaj yeem yog ib qho kev hloov pauv ntawm cov txheej txheem los xyuas kom meej kev tswj hwm ntawm kev tiv thaiv kab mob tiv thaiv kab mob thaum kis kab mob. Tsis tas li ntawd, hauv vitro, cov kev tshawb fawb pom tau tias txo qis IFN-ß txhawb nqa kev ua haujlwm los ntawm HCV-induced autophagy hauv cov cell.79
Hauv cov ntsiab lus, IFN teeb liab, ua rau kev qhia ntawm ISGs, yog qhov tseem ceeb rau kev tswj hwm tus kab mob kis kab mob ua rau nws lub hom phiaj tsim nyog rau HBV, HCV thiab HDV kom khiav tawm lub cev tiv thaiv kab mob thiab teeb tsa kev kis tus kab mob tsis tu ncua.
3.3|Modulating lub cev tiv thaiv kab mob
Cov kab mob kab mob siab kuj tseem muaj peev xwm hloov kho tus naj npawb ntawm lub cev tiv thaiv kab mob hauv lub cev nrog kev ua haujlwm tiv thaiv kab mob, los ntawm (i) nce cov tshuaj tiv thaiv kab mob los yog (ii) inhibition ntawm kev loj hlob / induction ntawm apoptosis.
Piv txwv li, Myeloid-Derived Suppressor Cells (MDSCs), piv txwv li, nyiam qhov chaw tiv thaiv kab mob. Lawv tau pom dav dav mus rau lub siab hauv cov neeg mob HBV-80,81 nrog rau kev nce ntxiv hauv cov neeg mob uas muaj HCV-82 (Daim duab 3-A). Hauv cov neeg mob CHB, kev nce hauv MDSC kuj tau txuas nrog txo T-cell activation.80,81 Ntawm kev ceeb toom, nce cov hlwb pro-inflammatory kuj tuaj yeem ua rau cov kab mob tsis zoo raws li pom hauv CHB cov neeg mob, qhia txog kev sib raug zoo ntawm ILC1 tus lej thiab cov kab mob siab 10 (Daim duab 3 A).
Ntawm qhov tsis sib xws, cov neeg mob HCV ntev qhia cov kab mob siab NK cell qis, tom qab nce KLRG1 (ib qho lymphocyte co-inhibitory receptor) qhia 83 (Daim duab 3A). KLRG1 qib inversely txuam nrog lub peev xwm ntawm NK hlwb kom proliferate thiab tsim IFN. Innate-zoo li invariant NKT hlwb raug txo qis hauv cov neeg mob CHB, thiab cov seem ntawm cov iNKT cov hlwb ua kom pom tsis zoo hauv kev teb rau nws qhov tshwj xeeb agonist 84 (Daim duab 3A). Tsis tas li ntawd, MAIT cov hlwb raug txo qis hauv cov ntshav ntawm cov neeg mob uas muaj kab mob HBV, HCV thiab HDV thiab hauv HCV / HIV co-infection85 (Daim duab 3A). Hauv cov neeg mob HBV, tus naj npawb ntawm daim siab MAIT hlwb inversely correlates nrog daim siab fibrosis thiab o.11 Induction ntawm MAIT apoptosis los ntawm cov kab mob no, txawm li cas los xij, tsis tau pom thiab lub cell txo qis tau piav qhia los ntawm kev ua kom lub cev tsis muaj zog thaum muaj kab mob ntev.
Ntxiv nrog rau cov xov tooj ntawm tes, cov kab mob tsim cov tswv yim los cuam tshuam nrog lub cev tiv thaiv kab mob polarization (xws li pro-inflammatory vs. anti-inflammatory phenotypes) thiab tshwj xeeb, cytokine secretion profile, ib qho tseem ceeb ntawm kev tiv thaiv kab mob ntawm tes phenotypes. Qhov tseeb, ua kom cov tshuaj tiv thaiv kab mob ua rau muaj kev tiv thaiv kab mob thaum inhibiting pro-inflammatory secretions muaj qhov tolerogenic ib puag ncig zoo rau kev tsim kab mob thiab kev saib xyuas.
Pro-inflammatory cytokines xws li PBMC-derived IL-12 (ex vivo stimulation) thiab/los yog MAIT cell-derived IFNy thiab TNF yog downregulated nyob rau hauv mob HBV thiab HCV neeg mob85,86 (Daim duab {{6}) }B, point#1-2). Kev txo qis ntawm lwm cov cytokines xws li IL-1 , TNF , IL-6 los yog IFN-I feem ntau tau piav qhia hauv vitro (xws li tib neeg KCs), siv virions lossis cov kab mob tshwj xeeb, tab sis kuj tuaj yeem pab txhawb rau cov kab mob. txo cov tshuaj tiv thaiv kab mob uas pom hauv HBV thiab HCV cov neeg mob8,87 (Daim duab 3-B, point#1,3).
Ntawm qhov tod tes, cov tshuaj tiv thaiv kab mob cytokines (IL-10, TGF- ) thiab/los yog cov cim saum npoo (CD163) raug kho rau cov neeg mob uas muaj HBV8,86,88 (Daim duab 3-B , point#4-5) as well as inpatient sera and in vitro model of HCV infection (Daim duab 3-B, point#4).89
Cov kab mob kab mob siab ntxiv ua rau lub cev tiv thaiv kab mob los ntawm kev hloov kho ntawm qhov chaw receptors thiab lawv cov ligands cuam tshuam rau lub cev tiv thaiv kab mob, inhibition thiab apoptosis. Tseeb, FasL upregulation tau pom nyob rau hauv HBV cov neeg mob 'KCs, nyiam cell death90 (Daim duab 3B, point #6). Ntawm cov ntawv ceeb toom, cov kev soj ntsuam zoo sib xws tau pom nrog lwm cov kab mob kis tab sis tseem tsis tau lees paub hauv cov neeg mob.87 Ntau qhov tseeb yog qhov kev nthuav qhia ntawm inhibitory checkpoint proteins / receptors, impairing CD8 plus T cell thiab NK cell kev ua thiab yog li tiv thaiv kab mob tiv thaiv kab mob. , uas tau pom ntawm daim siab los ntawm cov neeg mob CHB (ie PD-1) thiab MAIT hlwb ntawm cov neeg mob HBV thiab HCV (ie PD-1, CTLA-4). Qhov kev nthuav qhia no qhia txog lub cev tsis muaj zog ntawm tes phenotype91-93 (Daim duab 3B, point #7). NK cell activation tseem raug cuam tshuam ncaj qha los ntawm kev txo qis ntawm cov activating receptor NKG2D hauv HCV89 thiab CHB cov neeg mob94 (Daim duab 3B, point #8). Tsis tas li ntawd, HCV txo qis kev qhia ntawm cov activating receptors NKp46 thiab NKp30 hauv vitro 95 (Daim duab 3B, point # 9).
Thaum kawg, DC ua kom thiab tsiv teb tsaws mus rau cov qog nqaij hlav hauv nruab nrog cev, uas yog qhov tseem ceeb rau kev ua kom lub cev tiv thaiv kab mob, yog qhov tsis zoo rau cov neeg mob HCV.73,96.
Yog li, HBV, HCV thiab HDV tuaj yeem hloov kho tus lej, phenotype thiab cov lus teb ntawm lub cev tiv thaiv kab mob hauv lub cev los tsim kom muaj qhov tolerogenic ib puag ncig uas ua rau lymphocyte ua kom tsis zoo. Yog li ntawd, cov kab mob no tuaj yeem tswj tau tus kab mob mus ntev rau ntau xyoo, ua rau muaj kev tswj tsis tau tus kab mob, xws li HCC.
4|TXOJ CAI NTAWM LUB TSEV KAWM NTAWV NTAWM KEV HLOOV HLOOV HLOOV SAIB XYUAS
Muaj ntau txoj kev kho mob uas twb muaj lawm tiv thaiv kab mob siab kab mob siab. Cov kev kho mob no tuaj yeem tsom mus rau cov kauj ruam sib txawv ntawm cov kab mob hauv lub neej, xws li kab mob nkag mus (bulevirtide tiv thaiv HBV thiab HDV…), replication (nucleos(t)ides analogues tawm tsam ntau yam kab mob…) thiab egress (Nucleic Acid Polymers tiv thaiv HBV, HCV thiab HDV. ). Txawm li cas los xij, txawm tias cov kev kho mob no muaj txiaj ntsig zoo los tswj tus kab mob, lawv feem ntau tsis txaus los tshem tawm tag nrho thiab / lossis tuaj nrog cov kev mob tshwm sim muaj zog. Yog li ntawd, kev txhim kho cov kev kho tshiab tseem yuav tsum tau ua.
Kev siv zog loj tau ua nyob rau hauv kaum xyoo dhau los los tshem tawm kab mob siab kab mob siab thiab tshwj xeeb tshaj yog kab mob siab ntev. Tsis ntev los no, kev kho mob uas ua rau kev tswj hwm thiab tshem tawm HCV tau tsim. Glecaprevir thiab pibrentasvir (MAVIRET) tsom rau cov kab mob kis kab mob NS3/4A thiab NS5A, uas, raws li tau piav qhia hauv qhov kev tshuaj xyuas no, tau koom nrog ntau lub cev tiv thaiv kab mob thiab tau pom tias muaj txiaj ntsig zoo hauv kev txo cov kab mob kis tau ntev, phenotype.97. Tus nqi ntawm kev kho mob no txwv nws txoj kev nkag mus tau rau txhua tus neeg mob HCV. Cov kev siv zog zoo sib xws tau ua los nrhiav kev kho rau CHB- thiab HDV-cov neeg mob. Txawm hais tias ob peb hom DAA (xws li Bulevirtide, Lonafarnib, capsid modulators. …)98-100 tam sim no tab tom tshawb nrhiav rau kev kho mob ntawm cov neeg mob no, tsis muaj leej twg tau pom muaj txiaj ntsig zoo hauv vivo tseem.
Thaum muaj kev siv zog los tsim cov DAAs tshwj xeeb los tsom cov kab mob no, lwm qhov kev kho mob tau ua raws, uas yog kev kho dua tshiab thiab / lossis kev hloov pauv ntawm lub cev tiv thaiv kab mob.
Cov kev kho mob zoo li no tuaj yeem siv los ua mono- lossis kev kho mob uas twb muaj lawm (piv txwv li DAAs). Qhov tseeb, thawj qhov kev txo qis ntawm cov kab mob hauv lub cev tsis muaj zog nrog DAA thiab tom qab ntawd ua kom lub cev tiv thaiv kab mob yuav yog qhov tseem ceeb ntawm kev tshem tawm tus kab mob siab kab mob siab, raws li tau hais tseg rau kev tshem tawm HBV.101 Qhov tseem ceeb, txoj hauv kev tiv thaiv kab mob tshwj xeeb uas tsis zoo los ntawm cov kab mob yuav tsum yog. suav nrog hauv kev txhim kho ntawm kev kho mob. Tseeb tiag, lawv tuaj yeem yog qhov tshwm sim ntawm kev hloov pauv ntawm cov txheej txheem los ua kom muaj sia nyob ntawm tus kab mob, qhia tias lawv qhov kev ua kom muaj peev xwm tshem tawm tus kab mob.
Ua ntej nyob rau hauv txoj kab nrog xws li, broadly neutralizing antibodies (bNAbs) yog dav soj ntsuam, nrog rau ob qho tib si nkag-inhibiting thiab neutralizing kev ua ub no.102 bNAbs cais los ntawm HCV-rov qab cov neeg mob pom tau zoo neutralization kev ua ub no tiv thaiv HCV.103,104 Yog li, bNAbs yuav tsum tau envisaged. pathway escape (ie eHAV, eHEV and HBV; Table 1). Txawm li cas los xij, antibody-dependent enhancement (ADE) sawv cev rau qhov kev sib tw loj hauv kev txhim kho bNAbs. Qee cov kab mob siv 'neutralizing' cov tshuaj tiv thaiv tsis zoo (nrog rau kev ua haujlwm tsis muaj zog thiab / lossis cov ntshav qis) kom kis tau lub cell ntawm FcR-dependent mechanism.105,106
Tsis tas li ntawd, qhov sib npaug tsis yooj yim ntawm cov lus teb pro- thiab cov tshuaj tiv thaiv kab mob yog qhov tseem ceeb rau kev tshem tawm cov kab mob thiab tiv thaiv daim siab puas. Muaj ntau txoj hauv kev tuaj yeem pom los tiv thaiv cov kab mob 'kev ua haujlwm ntawm cov lus teb inflammatory.
Ntawm ib sab, qhov nce hauv cov lus teb pro-inflammatory tuaj yeem ua tiav los ntawm ntau txoj kev. Kev kho mob nrog PRR agonists tau raug txiav txim siab ntau nyob rau hauv kaum xyoo dhau los vim lawv tuaj yeem (i) ua rau muaj cov kab mob pro-inflammatory cytokines thiab lwm yam tshuaj tiv thaiv kab mob, (ii) nce los ntawm kev tawm tswv yim zoo voj kev qhia ntawm cov sensors nws tus kheej, ( iii) hloov kho cov phenotypes ntawm tes (tiv thaiv kev tiv thaiv kev tiv thaiv) thiab (iv) txaus siab rau kev nrhiav neeg ua haujlwm ntawm lwm lub cev tiv thaiv kab mob. Niaj hnub no, PRR agonists feem ntau yog siv los ua cov tshuaj tiv thaiv kab mob, tab sis lawv tau raug suav tias yog cov neeg sawv cev ib leeg. Ntau qhov kev sim hauv vitro thiab hauv vivo ntawm cov agonists tam sim no tseem tab tom ua nyob rau hauv cov ntsiab lus ntawm kab mob siab kab mob siab, thiab qee qhov twb tau sim hauv kev sim tshuaj kho mob 107-116 (Table 1). Kev txuas ntxiv ntawm cov kev sim no rau cov kab mob uas paub txog dysregulate muab txoj hauv kev yuav tsum tau txiav txim siab, raws li TLR3 agonists tiv thaiv kab mob HBV, txij li HBV txo TLR3 qhia hauv cov neeg mob110 (Table 1).
Tsis tas li ntawd, kev tswj hwm ncaj qha ntawm cov neeg kho mob inflammatory tau siv ntau xyoo los kho cov kab mob kis kab mob (xws li peg-IFN tiv thaiv HBV thiab HDV), tab sis nws qhov kev ua tau zoo tsawg (piv txwv li tus nqi qis ntawm kev tshem tawm cov kab mob) thiab cov kev mob tshwm sim tsis zoo. ua kom nws ua tus neeg sawv cev zoo rau yav tom ntej ntawm kev kho tus kab mob siab kab mob siab. Tau ntau xyoo lawm, lwm tus neeg kho mob inflammatory tau raug sim rau kev kho tus kab mob siab kab mob siab tab sis tau pom tias muaj kev ua tau zoo lossis tsis muaj txiaj ntsig ntxiv piv rau cov kev kho mob uas twb muaj lawm (xws li IFN tiv thaiv HBV). Lwm cov kws kho mob pro-inflammatory uas muaj peev xwm tiv thaiv kab mob ntau dua tuaj yeem pom tau (xws li IL-1 , lymphotoxin receptor).117,118 Txawm li cas los xij, qhov ntau thiab lub sijhawm ntawm cov kev kho mob no yuav tsum tau nruj me ntsis saib xyuas raws li lub sijhawm tsis muaj kev tiv thaiv kab mob tuaj yeem ua rau. mus rau cov kev mob tshwm sim loj heev xws li cytokine storms.119,120 Lwm qhov teeb meem uas yuav tsum tau xav txog yog qhov kev hais lus tsim nyog ntawm lub siab thiab kev siv cov kev kho mob uas tau hais tseg, uas tseem tshuav, rau hnub tim, ib qho teeb meem nyuaj. Tseeb tiag, kev tswj hwm txoj hlab ntshav tsis tsim nyog rau kev kho mob mus sij hawm ntev, tshwj xeeb tshaj yog thaum xav txog cov tshuaj tiv thaiv kab mob, thaum kev tswj hwm qhov ncauj yuav tsum muaj kev hla ntawm phab ntsa hauv plab.
Ntxiv rau qhov ua kom muaj cov tshuaj tiv thaiv kab mob, txo cov tshuaj tiv thaiv kab mob yuav ua kom txaus lossis tsawg kawg yog thawj kauj ruam ntawm kev ua kom lub cev tiv thaiv kab mob ua haujlwm. Kev tiv thaiv ncaj qha ntawm cov tshuaj tiv thaiv kab mob cytokines (xws li TGF- , IL-10) los ntawm cov molecules me me los yog cov tshuaj tiv thaiv tsis zoo, tau pom tias muaj txiaj ntsig zoo hauv kev kho mob ntau yam qog noj ntshav thiab yuav tsum tau saib xyuas rau cov kab mob siab uas tsom cov lus teb no (xws li HBV)121-123 (Table 1). Tsis tas li ntawd, ob peb lub molecules tau siv los tsom cov tshuaj tiv thaiv phenotype feem ntau tshwm sim los ntawm cov qog nqaij hlav macrophages (TAMs), raws li tau piav qhia los ntawm lwm tus.124 Cov modulators no, uas feem ntau tsom cov cim saum npoo los yog cov txheej txheem metabolic tseem ceeb (ie anti-CSF1R lossis anti- CCR2 thiab CB839 feem), yuav tsum tau kuaj hauv kev tswj hwm tus kab mob HBV thiab HCV uas cov macrophages tso tawm cov phenotype zoo sib xws (Table 1). MDSCs, nrhiav neeg nyob hauv HBV thiab HCV kab mob, kuj yuav yog lub hom phiaj kho mob. Cov tswv yim, aiming ntawm depleting cov hlwb los yog inhibiting lawv nrhiav neeg ua hauj lwm yog tam sim no raug tsim, raws li qhia rau ib co kab mob siv Gemcitabine los yog LXR agonists, thiab lwm yam.125 Lwm txoj kev kho yog qhov sib txawv ntawm MDSCs rau hauv non-suppressive cell hom siv, piv txwv li. , tag nrho-trans retinoic acid, uas tau pom los kho cov lus teb los tiv thaiv kab mob thiab txwv tsis pub kis kab mob hauv cov hlwb los ntawm cov neeg mob HBV. Kev sim tshuaj nrog cov tshuaj tiv thaiv kab mob no tau ua tab sis cov ntaub ntawv txwv tsis pub muaj nyob rau tam sim no.126 Nyob rau tib lub sijhawm, nce kev nrhiav neeg ua haujlwm ntawm "zoo" lub cev tiv thaiv kab mob rau lub siab, tshwj xeeb yog DCs, yuav pab ua kom muaj zog tiv thaiv kab mob thiab ua kom muaj zog. tshwj xeeb T cell. Kev nce DC suav thiab / lossis thim rov qab DC inhibition tau kawm nyob rau hauv cov kab mob sib txawv thiab yuav tsum tau txiav txim siab rau HCV kab mob, uas zoo sib xws yog pom 127 (Table 1). Ib yam li ntawd, kev hloov pauv ntawm NK cell suav tau pom cov txiaj ntsig tau zoo.128
Qhov kawg tab sis tsis kawg, kev hloov pauv ntawm inhibitory receptors tau siv los kho ntau yam qog noj ntshav thiab tuaj yeem / yuav tsum tau rov ua dua rau kev kho mob siab. Anti-PD-1/PD-L1 kev kho mob twb tau sim tawm tsam HBV thiab HCV kab mob uas txhim kho kev ua kom lub cev tiv thaiv kab mob ua haujlwm129,130 (Table 1). Txawm li cas los xij, cov ntaub ntawv los ntawm kev sim tshuaj nrog cov neeg mob tsis muaj mob qog noj ntshav tseem tsis tau paub. Tsis tas li ntawd, blockade ntawm lwm yam inhibitory receptors tau qhia txhawb nqa cov txiaj ntsig ntawm HBV kab mob, ib leeg lossis ua ke nrog anti-PD-1/PD-L1, thiab yog li yuav tsum tau txiav txim siab zoo ib yam.131 Tag nrho cov tswv yim no tau txais txiaj ntsig los ntawm kev sib xyaw ua ke nrog viremia-txo DAA, ua pov thawj qhov xav tau thiab kev ua haujlwm ntawm kev sib koom ua ke.
5|TEEB MEEM
Qhov kev tshuaj xyuas no piav qhia txog yuav ua li cas cov kab mob kab mob siab tau hloov zuj zus mus rau ntau txoj hauv kev kom tshem tawm cov kab mob hauv lub cev thiab tswj lawv cov kab mob hauv daim siab. Ntxiv mus, thaum peb tsuas tham txog cov txiaj ntsig ntawm kab mob siab rau lub siab lub cev tiv thaiv kab mob hauv lub cev, cov phenotypes / cov txheej txheem tuaj yeem pom hauv lwm cov kab mob hauv siab, xws li lwm yam kab mob, kab mob thiab kab mob. Kev kho lub hom phiaj ib lossis ob peb lub tswv yim no tuaj yeem txhim kho kev ua tau zoo ntawm cov kev kho mob uas twb muaj lawm lossis ua rau kev txhim kho cov kev kho tshiab kom tshem tawm cov kab mob siab.
Kev tsis sib haum xeeb ntawm kev txaus siab
Cov neeg sau ntawv tsis muaj teeb meem ntawm kev txaus siab los tshaj tawm.
AUTHORS 'CONTRIBUTION
Cov ntaub ntawv curation: MD, MDS thiab SS. Cov ntawv sau: MD, MDS, SS, MH, DD thiab SFD. Daim duab npaj: MD.
DAIM NTAWV THOV KEV PAB CUAM
Cov ntaub ntawv muaj nyob rau ntawm tus kws sau ntawv, Dr Suzanne Faure-Dupuy, raws li kev thov tsim nyog.
REFERENCES
1. Wisplinghoff H, Appleton DL. Kab mob ntawm daim siab. Hauv: Weber O, Protzer U, eds. Sib piv kab mob siab. Birkhäuser; 2008. p. 143-160. doi: 10.1007/978-3-7643-8558-3_8
2. Ekpanyapong S, Reddy KR. Cov kab mob fungal thiab kab mob parasitic ntawm daim siab. Gastroenterol Clin North Am. 2020;49:379-410.
3. Lanini S, Ustianowski A, Pisapia R, Zumla A, Ippolito G. Viral kab mob siab: aetiology, epidemiology, kev sib kis, kev kuaj mob, kev kho mob, thiab kev tiv thaiv. Kab mob Dis Clin North Am. Xyoo 2019; 33:1045-1062.
4. Alfaiate D, Clément S, Gomes D, Goossens N, Negro F. Chronic hepatitis D thiab hepatocellular carcinoma: kev tshuaj xyuas thiab kev tshuaj xyuas meta-kev soj ntsuam ntawm kev soj ntsuam. J Hepatol. Xyoo 2020; 73: 533-539.
5. Kamar N, Izopet J, Dalton HR. Kab mob siab kab mob siab E kab mob thiab kev kho mob. J Clin Exp Hepatol. 2013; 3:134-140.
6. Racanelli V, Rehermann B. Lub siab yog lub cev tiv thaiv kab mob. Hepatology. 2006; 43:S54-S62.
7. Faure-Dupuy S, Vegna S, Aillot L, et al. Tus cwj pwm ntawm tus qauv lees paub receptor qhia thiab kev ua haujlwm hauv lub siab thawj cov hlwb thiab muab cov kab ntawm tes. J Innate Immun. 2018; 10:339-348.
8. Faure-Dupuy S, Delphin M, Aillot L, et al. Tus kab mob siab B-induced modulation ntawm daim siab macrophage muaj nuj nqi txhawb cov kab mob hepatocyte. J Hepatol. Xyoo 2019; 71: 1086-1098.
9. Ishibashi H, Nakamura M, Komori A, Migita K, Shimoda S. Cov kab mob siab, kev ua haujlwm ntawm tes, thiab kab mob. Semin Immunopathol. Xyoo 2009; 31:399.
10. Liu M, Zhang C. Lub luag hauj lwm ntawm innate lymphoid hlwb hauv lub cev tiv thaiv kab mob hauv siab. Pem hauv ntej Immunol. Xyoo 2017; 8:695.
11. van Wilgenburg B, Scherwitzl I, Hutchinson EC, et al. MAIT hlwb tau qhib thaum tib neeg kis kab mob. Nat Commun. Xyoo 2016; 7: 11653.
12. Gulati A, Kaur D, Krishna Prasad GVR, Mukhopadhaya A. PRR muaj nuj nqi ntawm innate immune receptors nyob rau hauv kev paub txog cov kab mob los yog kab mob ligands. Adv Exp Med Biol. 2018;1112:255-280.
13. Luangsay S, Ait-Goughoulte M, Michelet M, et al. Kev nthuav qhia thiab kev ua haujlwm ntawm Tus Xov Tooj- thiab RIG-zoo li receptors hauv HepaRG hlwb. J Hepatol. Xyoo 2015; 63: 1077-1085.
14. Blum JS, Wearsch PA, Cresswell P. Pathways of antigen processing. Annu Rev Immunol. 2013; 31:443-473.
15. Sun SC. Txoj kev tsis-canonical NF-κB hauv kev tiv thaiv kab mob thiab mob. Nat Rev Immunol. 2017; 17:545-558.
16. Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol. 2017;198:1006-1014. 17. Mesev EV, LeDesma RA, Ploss A. Kev txiav txim siab hom I thiab III interferon signaling thaum kis kab mob. Nat Microbiol. Xyoo 2019; 4: 914-924.
18. Poisson J, Lemoinne S, Boulanger C, et al. Lub siab sinusoidal endothelial hlwb: physiology thiab lub luag hauj lwm nyob rau hauv daim siab kab mob. J Hepatol. Xyoo 2017; 66:212-227.
19. Breiner KM, Schaller H, Knolle PA. Endothelial cell-mediated uptake ntawm tus kab mob siab B: lub tswv yim tshiab ntawm daim siab tsom rau cov kab mob hepatotropic. Hepatology. 2001; 34:803-808.
20. Pöhlmann S, Zhang J, Baribaud Frédéric, et al. Tus kab mob siab C glycoproteins cuam tshuam nrog DC-SIGN thiab DC-SIGNR. J Virol. 2003; 77:{5}}.
21. Pohlmann S, Soilleux EJ, Baribaud F, et al. DC-SIGNR, DC-SIGN homologue qhia hauv cov hlwb endothelial, khi rau tib neeg thiab simian cov kab mob tiv thaiv kab mob thiab ua kom muaj kab mob hauv trans. Proc Natl Acad Sci USA. 2001; 98:{5}}.
22. Gardner JP, Durso RJ, Arrigale RR, et al. L-SIGN (CD 209L) yog lub siab tshwj xeeb ntes receptor rau tus kab mob siab C. PNAS. 2003; 100:4498-4503.
23. Geijtenbeek TBH, Kwon DS, Torensma R, et al. DC-SIGN, ib qho dendritic cell-specific HIV-1-binding protein uas txhim khu kev kis kab mob ntawm T hlwb. Cell. 2000; 100:587-597. 24. Halary F, Amara A, Lortat-Jacob H, et al. Tib neeg cytomegalovirus khi rau DC-SIGN yog xav tau rau kev kis kab mob dendritic cell thiab lub hom phiaj ntawm kev kis kab mob. Kev tiv thaiv. 2002; 17:653-664.
25. Di Lorenzo C, Angus AGN, Patel AH. Kab mob siab C evasion mechanisms los ntawm neutralizing antibodies. Kab mob. 2011; 3:2280-2300.
26. Rosbjerg A, Genster N, Pilely K, Garred P. Evasion mechanisms siv los ntawm cov kab mob kom dim txoj kev lectin ntxiv. Pem hauv ntej Microbiol. Xyoo 2017; 8:868.
27. Feng Z, Lemon SM. Peek-a-boo: membrane hijacking thiab pathogenesis ntawm viral kab mob siab. Trends Microbiol. 2014; 22:59-64.
28. Agrawal P, Nawadkar R, Ojha H, Kumar J, Sahu A. Ua kom tiav cov tswv yim evasion ntawm cov kab mob: kev saib xyuas. Pem hauv ntej Microbiol. 2017: 8: 1117–1136.
29. Conde JN, Silva EM, Barbosa AS, Mohana-Borges R. Cov txheej txheem ntxiv hauv cov kab mob flavivirus. Pem hauv ntej Microbiol. 2017; 8:213–220.
30. Zhang R, Liu Q, Liao Q, Zhao Y. CD59: lub hom phiaj cog lus rau kev kho mob qog noj ntshav. Yav tom ntej Oncol. 2018; 14:781-791.
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