Tus tswv tsev Antiviral Teb Tawm tsam Avian Infectious Bronchitis Virus (IBV): Tsom ntsoov rau Innate Immunity Part 3
Feb 20, 2024
4.1. IBV Infection Triggered Interferon Activation
IFNs, suav nrog hom I, hom II, thiab hom III IFNs [71], muaj ntau yam hauv lub cev tsis muaj zog.
Hom III interferon (IFN) yog ib qho tseem ceeb ntawm kev tiv thaiv kab mob uas muaj cov tshuaj tiv thaiv kab mob, tshuaj tiv thaiv kab mob, thiab tshuaj tiv thaiv kab mob. Cov kev tshawb fawb tsis ntev los no tau pom tias hom III IFN kuj muaj qhov cuam tshuam zoo rau kev paub txog kev ua haujlwm thiab kev nco txhim kho.
Hais txog kev paub txog kev ua haujlwm thiab kev nco, lub luag haujlwm tseem ceeb ntawm hom III IFN yog los txhawb kev loj hlob thiab kev sib txuas ntawm cov paj hlwb, txhim kho qhov sib npaug ntawm cov neurotransmitters, thiab txhim kho kev tiv thaiv kab mob ntawm cov neurons, yog li ua rau lub hlwb hlwb muaj zog thiab agile, thiab txhim kho. nco thiab xav. muaj peev xwm. Tsis tas li ntawd, hom III IFN kuj tseem tuaj yeem txhawb kev hloov pauv ntawm cov kab mob neural qia hlwb mus rau ib puag ncig, nce kev tsim thiab loj hlob ntawm cov neurons tshiab, pab lub hlwb nyob hauv cov hluas thiab noj qab haus huv, thiab tiv thaiv cov kab mob neurodegenerative xws li Alzheimer's disease.
Tsis tas li ntawd, hom III IFN tseem tuaj yeem txo qis kev nco thiab kev paub txog kev ua haujlwm los ntawm kev tswj hwm kev sib cuam tshuam ntawm lub cev tsis muaj zog thiab lub paj hlwb, inhibiting lub hlwb cov lus teb, thiab tiv thaiv neurons los ntawm kev puas tsuaj.
Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias qhov cuam tshuam ntawm hom III IFN muaj feem cuam tshuam nrog kev siv tshuaj. Tus nqi tsim nyog ntawm hom III IFN tuaj yeem pab txhim kho kev txawj ntse thiab kev nco, tab sis cov khoom siv ntau dhau ntawm hom III IFN tuaj yeem ua rau cov lus teb inflammatory, puas hlwb hlwb thiab neural tes hauj lwm, thiab ua rau kev nco poob.
Ua ke, kev sib raug zoo ntawm hom III IFN thiab kev nco yog qhov zoo. Kev txhaj tshuaj tsim nyog ntawm hom III IFN tuaj yeem ncua lub hlwb kev laus thiab pab tswj kev paub zoo thiab kev nco. Txawm li cas los xij, thaum siv hom III IFN, qhov ntau npaum li cas yuav tsum tau tswj nruj me ntsis kom tsis txhob siv ntau dhau kom tsis txhob muaj hluav taws kub. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.
Nyem Paub Short-term Nco yuav ua li cas txhim kho
Feem ntau, hom I IFNs (IFN- , IFN- , thiab lwm yam) thiab hom III IFNs (IFN-λ) tau raug pov thawj rau kev tiv thaiv kab mob, thaum hom II IFNs (IFN-) tuaj yeem qhib T hlwb thiab macrophages [72]. Kuv IFN ua haujlwm raws li lub zog muaj zog tiv thaiv kab mob, uas koom nrog cov tswv teb teb tom qab IBV kab mob.
Nws tau pom tias IFN- tuaj yeem inhibitrespiratory Beaudette lossis Grey IBV hom ob leeg hauv vitro thiab hauv vivo [73].
Cov kev tshawb fawb hauv vitro tau qhia tias qhov induction ntawm IFN- yog nyob rau hauv MDA5-raws li [56]. Nyob rau theem pib kis kab mob (9 hp), IFN- tau tswj hwm thaum kis tus kab mob neuropathogenicIBV strain [55]. Txawm li cas los xij, thaum siv cov kab mob ua pa M41 IBV, kev qhia ntawm IFN- hauv CEK hlwb tau ncua mus txog 12 dpi, thaum cov khoom siv protein 5b tau koom nrog hauv kev cuam tshuam ntawm tus tswv tsev kaw uas ua rau txo qis ntawm IFNs [74].
Tsis tas li ntawd, tus kab mob ua paBeaudette IBV tau pom tias cuam tshuam nrog IFN- -induced translocation ntawm STAT1 thiab STAT1 phosphorylation hauv Vero hlwb thaum lub sij hawm kis kab mob (18 dpi), ref. [74] qhia txog kev ua pa ntawm IBV-mediated inhibition ntawm IFN signaling nyob rau hauv lub sij hawm-dependentmanner.
Qhov sib txawv ntawm IFN qhia ntawm kev ua pa thiab neuropathogenic IBVinfections xav tau kev ua haujlwm yav tom ntej, uas yuav pab kom nkag siab txog cov txheej txheem hauv qab ntawm cov ntaub so ntswg tropism ntawm cov kab mob IBV sib txawv. ntawm 1 dpi hauv spleens tom qab virulent ua pa IBV kab mob [62], thaum nyob rau hauv tracheas lub upregulation ntawm IFNs tsis tau soj ntsuam ntawm 3 dpi [61].
Tsis tas li ntawd, cov qaib tau txhaj tshuaj tiv thaiv kab mob ua pa M41 lossis LDT3 muaj zog dua hom I IFNlevels, raws li [61]. Kev ua phem ntawm IBVs yuav yog vim li cas rau qhov sib txawv hauv IFN qib. Raws li cov txiaj ntsig hauv PRR qhia, cov txiaj ntsig no tseem qhia tias nws tseem ceeb heev uas yuav tsum tau coj mus rau hauv kev txiav txim siab hauv kev tswj hwm tus kab mob no.
Ib yam li hom I IFNs, nyob rau theem pib ntawm kev kis kab mob (12 dpi), tom qab inoculation nrog cov kab mob ntsws Conn IBV, IFN- tau txo qis hauv cov hlab ntsws thiab lub ntsws ntawm cov nqaij qaib [26]. Ntawm 2-3 dpi, thaum inoculated nrog ua pa M41 IBV strain, IFN- tau induced hauv tracheas thiab ntsws [35,75].
Txawm hais tias cov tshuaj tiv thaiv kab mob ntawm IFN- tawm tsam IBV tsis tau ua tiav tag nrho, raws li cov txiaj ntsig tau pom hauv avian influenzavirus (AIV) cov kab mob qaib, nws tau hais tias IFN- tuaj yeem cuam tshuam ncaj qha rau IBV rov ua dua los ntawm kev pib ntawm ISG-encoded ribonuclease L (RNase. L) [76].
Forexpression ntawm ISGs, cov kev tshawb fawb pom tau hais tias nyob rau hauv ntau yam xws li nqaij qaib embryos (6 hp), tracheas (3 dpi), thiab ob lub raum (5-6 dpi), upregulation ntawm ISGs tau nthuav tawm intranscriptional tsom xam tom qab kis tau tus kab mob sib txawv IBV hom [61] .
Los xaus, txawm hais tias cov lus teb ntawm IFNs tom qab IBV kab mob sib txawv nyob rau hauv ib qho kev sib txawv ntawm kev sib txawv thiab nyob ntawm lub sij hawm, feem ntau, kev ua kom IFNs yog txwv tsis pub nyob rau theem pib ntawm tus kab mob IBV kom tso cai rau kis kab mob.
Kev tswj hwm ntawm IFNs feem ntau tau soj ntsuam nrog qhib ISGs tom qab kis tau tus kab mob thaum lub cev tiv thaiv kab mob teb rau kev kis kab mob. Yog li ntawd, kev cuam tshuam ntxov thiab ua kom IFNs yog qhov tseem ceeb ntawm kev tswj tus kab mob.
4.2. Kab mob IBV ua rau lwm yam Cytokine thiab Chemokine Ua kom muaj zog
Lwm cov cytokines thiab chemokines kuj tseem yog cov tswj hwm tseem ceeb ntawm lub cev tsis muaj zog tiv thaiv kab mob. Piv txwv li, cuam tshuam nrog cov neeg ua haujlwm macrophages, kev tsim tawm ntawm IL-1 tau koom nrog hauv kev txo cov kab mob IBV hauv cov hlab ntsws [27].
Tsis tas li ntawd, kev txhim kho ntawm IFN- , IFN- , thiab IL12 ntawm 12 hpi, upregulation ntawm IFN- , IL -8, thiab macrophage inflammatory protein (MIP) -1 ntawm 48 hpi, thiab upregulation ntawm IFN- thiab IL-6 ntawm 72 hpi kuj tau pom, thiab kev tswj hwm ntawm cov cytokines no cuam tshuam nrog inhibition ntawm kev ua pa ntawm IBV Ark99 replication [77].
Nyob ntawm tus kab mob IBV, nws tau tshaj tawm tias proinflammatory cytokine qhia tau raug ntxias sib txawv hauv cov ntaub so ntswg sib txawv. Nyob rau hauv lub tracheas, thaum ntxov kis kab mob (1-3 dpi), kev qhia ntawm IL-1 , IL-10R2, IL-6, thiab LITAF tau elicited tom qab inoculation nrog ua pa los yog neuropathogenic IBV strains [61].
Qhov kev qhia ntawm IL-1 yog thawj zaug downregulated (12 hp) thiab sharply nce raws li tus kab mob IBV zuj zus nyob rau hauv lub tracheas thaum qaib tau inoculated nrog lub pa Conn IBV strain [26].
Tsis tas li ntawd, kev qhia ntawm IL-6 tau raug tswj hwm los ntawm p38 phosphorylation thaum lub sij hawm IBVinfection [78].Nyob raum, kev tswj ntawm cov cytokines no tsis cuam tshuam loj heev tom qab kis kab mob ua pa IS/885/{00-zoo li (885), M41 , thiab neuropathogenic QX-zoo li IBVstrains [79]. Cov qaib kis tau tus kab mob neuropathogenic IBV ntawm KIIa genotype nthuav qhia txog qib mRNA ntawm IL-6 thiab IL-1 ntawm 1 dpi hauv tracheas thiab ob lub raum, whereas qaib kis kab mob IBV kab mob ntawm ChVI genotype pom. sib piv me me upregulated mRNA qhia ntawm cov cytokines [80].
Tsis tas li ntawd, nyob rau hauv lub cev tiv thaiv kab mob splenic, kev qhia theem ntawm IL-7 thiab IL-18 tau nce qib ntawm 1 dpi tom qab ua pa ntawm IBV kab mob [62].Chemokines orchestrate kev tsiv teb tsaws ntawm cov hlwb thaum lub sij hawm soj ntsuam kev tiv thaiv kab mob. Mass IBVstrain stimulated gene expression of CXCR4, CCR6, chemokine-like receptor 1/CHEMR23, and Matrix metalloproteinase (MMPs) los ntawm cov theem pib ntawm kev kis kab mob (1 dpi) intracheas [58].
Cov chemokines no tuaj yeem ua lub luag haujlwm hauv kev tsiv teb tsaws ntawm activated T hlwb, uas yuav pab txhawb kom tshem tawm tus kab mob no ntxiv.Raws li cov kev soj ntsuam no, tom qab IBV kis tau tshwm sim, lub cev tiv thaiv kab mob tau qhib, uas ua rau kev nrhiav cov hlwb innate ntawm tus kab mob. cov chaw thiab kev txhim kho ntawm qhov sib txawv ntawm PPRs, cytokines, chemokines, thiab lwm yam. Txawm li cas los xij, kev txo qis ntawm PPRs (TLR7), IFNs (IFN- , IFN- ), thiab lwm yam cytokines (IL-1) tseem tau pom nyob rau theem ntxov heev. ofinfection (12 hp) los ntawm kev ua pa IBV hom, tawm tswv yim inhibition ntawm innate immunity yog ib qho tseem ceeb los tsim kom muaj kev vam meej IBV kab mob, uas tej zaum yuav muaj kev cuam tshuam cov tswv yim uas muaj tus kab mob coronaviruses yuav coj mus rau zam los ntawm tus tswv tsev innate tiv thaiv.
Vim tias feem ntau cov kev tshawb fawb tau ua tiav siv cov kab mob IBV ua pa, nws yuav yog ib qho tseem ceeb kom tau txais cov ntaub ntawv ntau ntxiv txog cov tshuaj tiv thaiv kab mob uas siv cov kab mob neuropathogenic IBV, uas yuav pab tsim cov tswv yim txhaj tshuaj thiab lwm yam kev cuam tshuam. Cov lus piav qhia dav dav ntawm cov lus teb hauv lub cev tiv thaiv kab mob IBV yog qhia hauv daim duab 1.
5. Apoptosis tshwm sim los ntawm IBV Kab Mob
Apoptosis yog ib qho ntawm cov txheej txheem tseem ceeb uas tsiaj siv los tiv thaiv kab mob. Nws kuj tseem tuaj yeem pab txhawb tus kab mob kis mus rau theem tom qab kis tus kab mob [81]. Muaj cov ntaub ntawv tshaj tawm txog IBV-induced apoptosis ob leeg hauv vivo [55] thiab hauv vitro [28,82].
Nws tau pom zoo tias thaj tsam IBV ORF1b yog lub luag haujlwm rau kev ua rau apoptosis [83].Nyob rau hauv cov qe ntshav, Bcl 2 tsev neeg cov proteins, suav nrog proapoptotic (Bax thiab Bak) thiab anti-apoptotic (Mcl 1, Bcl 2, thiab Bcl XL) proteins, modulated IBV-induced apoptosisat ib theem pib ntawm IBV kab mob [55].
Hauv IBV M41- kis HD11 thiab PBMCs-Mφ cov hlwb, kev nthuav qhia ntawm Bcl ntau dua -2 nrog rau kev nthuav qhia ntau ntxiv ntawm Bcl-2-koom X (Bax) qhia tias kis tus kab mob replication provokes apoptosis ntawm 48 hpi [ 28] ib. Nyob rau theem kawg ntawm kev kis kab mob, apoptosis tau pom los pab txhawb IBV replication. Xav txog IBV Beaudetteinfected DF-1 hlwb piv txwv li [84].
Hauv cov hlwb no, mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) txoj kev tau qhib; Txoj kev no tsis zoo los ntawm phosphatase DUSP6 [84]. Tsis tas li ntawd, lub unfolded-protein teb (UPR) sensor IRE1 -XBP1 txoj hauv kev kuj tau qhib rau theem lig.
6. Kev Pom Zoo hauv IBV Tswj
Txij li thaum thawj zaug tau sau tseg hauv Tebchaws Meskas hauv xyoo 1931, IBV tau dhau los ua thoob plaws hauv kev lag luam nqaij qaib [10]. Nws tau raug qhia tias lwm hom avian tuaj yeem ua lub luag haujlwm hauv kev sib kis ntawm IBV thoob ntiaj teb [86].
Piv txwv li, ib feem ntawm nucleotide ib nrab ntawm cov kab mob coronavirus cais tawm ntawm parrots (E. roratus) pom 100% homology nrog IBV GI-13 kab mob [87]. Txawm hais tias cov noog qus thiab cov avian coronaviruses ua rau muaj kev sib kis ntawm IBV yuav tsum muaj pov thawj ntxiv.
Nrog rau kev tshawb fawb txog kev txhaj tshuaj tiv thaiv thiab kev tiv thaiv, nyob rau xyoo tas los no tau tsom mus rau kev nkag siab txog kev tiv thaiv kab mob thaum ntxov tom qab tus kab mob IBV, vim qhov no yuav nthuav peb txoj kev paub txog kab mob ntawm tus kab mob, uas ua rau muaj txiaj ntsig zoo rau kev txhim kho kev tiv thaiv thiab tswj cov tswv yim. .
Innate kev tiv thaiv ua rau muaj kev sib koom tes los ntawm kev siv PPRs txhawm rau txheeb xyuas PAMPs, qhov chaw sib txawv xws li IFNs thiab proinflammatory cytokines ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob. Ntau qhov kev tshuaj xyuas txog kev tiv thaiv qaib cov lus teb rau tus kab mob IBV raug pom zoo rau kev nkag siab zoo ntawm tus kab mob tiv thaiv kab mob sib kis [55].
Muab ntau hom kab mob IBV, cov lus teb hauv lub cev tiv thaiv kab mob evoked los ntawm IBVinfection sib txawv nyob rau hauv strain-dependent thiab lub sij hawm-dependent yam. Txawm li cas los xij, kev cuam tshuam ntxov thiab kev ua kom muaj kev tiv thaiv hauv lub cev yog qhov tseem ceeb rau kev tswj tus kab mob. Txhawm rau ua kom lub cev tiv thaiv kab mob tsis ntev los no, agonists ntawm PRRs thiab IFNs tau nyiam ntau dua rau kev tsim tshuaj tiv thaiv tshiab. Tsis tas li ntawd, cov pej xeem muaj ntau haiv neeg ntawm tus kab mob no kuj pab txhawb kev txhim kho ntawm tus tswv tsev tiv thaiv, vim muaj ntau haiv neeg kis kab mob hauv cov tshuaj tiv thaiv ua rau muaj zog tiv thaiv kab mob hauv lub cev [88].
Yog li ntawd, rau kev nkag siab ntau ntxiv ntawm IBV-tus tswv tsev hauv kev tiv thaiv kev tiv thaiv kev sib raug zoo thiab kev txhim kho yav tom ntej ntawm kev tiv thaiv thiab tswj cov tswv yim, IBV cov qauv pej xeem, kev sib txawv ntawm kab mob genome, thiab kab lis kev cai, nrog rau cov xwm txheej ntawm cov tsiaj txhu yuav tsum tau muab coj los xav.
Txawm hais tias cov ntaub ntawv ntawm IBV-host innate tiv thaiv kev sib cuam tshuam tseem raug txwv vim tsis muaj kev sim ntsuas hauv qaib, nws tau pom zoo tias kev tiv thaiv kab mob hauv lub cev tsis yog tsuas yog rau kev tiv thaiv kev txhim kho tab sis kuj rau cov kab mob ntawm tus kab mob. Rau kev tswj hwm tus kab mob zoo, kev txhim kho ntxov ntawm tus tswv tsev lub cev tiv thaiv kab mob tseem ceeb heev.
Tsis tas li ntawd, vim hais tias tus qaib lub cev tiv thaiv kab mob ua rau muaj kev sib kis-nyob ntawm lub sijhawm thiab nyob ntawm lub sijhawm tom qab tus kab mob IBV, kev kuaj mob ntxov ntawm tus kab mob IBV kuj tseem ceeb rau kev tswj tus kab mob zoo dua. Kev tshawb nrhiav ntxiv yog yuav tsum tau tshawb nrhiav qhov sib txawv ntawm lub cev tiv thaiv kab mob tshwm sim los ntawm cov kab mob IBV sib txawv nrog cov kab mob sib txawv thiab cov kab mob.
Sau Kev Koom Tes: Kev npaj sau ntawv, YZ; Hloov kho, YZ, ZX; Kev saib xyuas, YC; FundingAcquisition, YZ Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Cov Nyiaj Txiag: Txoj kev tshawb no tau txhawb nqa los ntawm Doctoral Initiative Project ntawm Natural Science Foundationof Guangdong Province (18zxxt49), thiab Guangdong Basic thiab Applied Basic Research Foundation (2019B1515210026).
Institutional Review Board Statement: Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.
Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.
Kev tsis sib haum xeeb ntawm kev txaus siab: Cov kws sau ntawv tshaj tawm tias lawv tsis muaj nyiaj txiag lossis kev sib raug zoo ntawm tus kheej nrog lwm tus neeg lossis cov koom haum uas tuaj yeem cuam tshuam rau txoj haujlwm. Tsis muaj kev tshaj lij lossis lwm yam kev nyiam ntawm tus kheej ntawm ib qho xwm txheej lossis zoo hauv ib yam khoom, kev pabcuam, thiab / lossis lub tuam txhab uas tuaj yeem txhais tau tias muaj kev cuam tshuam rau txoj haujlwm uas tau hais hauv qhov kev tshuaj xyuas no. Cov kws sau ntawv tsis muaj kev lag luam orassociative txaus siab uas sawv cev rau qhov tsis sib haum xeeb ntawm kev txaus siab nrog rau cov haujlwm xa.
Cov ntaub ntawv
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