Kab mob thiab kab mob sib kis nyob rau hauv txoj hnyuv: Kev sib tw Scenario thiab lawv cov txiaj ntsig ntawm kev tiv thaiv tus tswv

Abstract:Cov kab mob thiab kab mob yog ob qho tib si cov kab mob tseem ceeb ua rau mob plab hnyuv, thiab kev tshawb fawb ntawm lawv cov txheej txheem pathogenic yuav tsom mus rau ib tus kab mob ib leeg. Txawm li cas los xij, kab mob thiab kab mob sib kis tshwm sim ntau zaus hauv chaw kho mob, thiab kev kis kab mob los ntawm ib tus kab mob tuaj yeem cuam tshuam qhov mob hnyav ntawm lwm tus kab mob, ncaj qha lossis tsis ncaj. Lub xub ntiag ntawm synergistic lossis antagonistic cuam tshuam ntawm ob kab mob hauv kev sib koom ua ke tuaj yeem cuam tshuam cov kab mob mus rau qhov sib txawv. Lub triad ntawm cov kab mob-viral-gut kev sib cuam tshuam muaj ntau yam ntawm inflammatory thiab tiv thaiv kab mob, autoimmunity, noj zaub mov tsis zoo, thiab lub plab microbiome. Hauv qhov kev tshuaj xyuas no, peb tau tham txog cov xwm txheej sib txawv uas tshwm sim los ntawm kev txiav txim sib txawv ntawm cov kab mob thiab cov kab mob hauv lub plab thiab tau piav qhia txog cov txheej txheem ua tau zoo ntawm kev sib koom ua ke lossis kev tawm tsam koom nrog hauv lawv txoj kev sib kis. Peb kuj tau tshawb nrhiav cov txheej txheem tswj hwm ntawm cov kab mob-viral co-kab mob ntawm tus tswv tsev hauv plab hnyuv tiv thaiv los ntawm ntau qhov kev xav.

Ntsiab lus: kab mob-viral co-kab mob; teeb liab kis tau tus mob; autoimmunity; noj zaub mov tiv thaiv kab mob; plab hnyuv microbiome

cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob

1. Taw qhia

Kev mob raws plab yog ib qho ua rau muaj kev mob tshwm sim thiab kev tuag ntawm tib neeg thoob ntiaj teb [1], uas muaj kev cuam tshuam ntau dua rau cov menyuam yaus hnub nyoog qis dua 5 xyoos [2–4]. Ntxiv nrog rau tib neeg kab mob, ntau yam nqaij qaib thiab tsiaj txhu hauv tsev poob lawv cov txiaj ntsig kev lag luam vim mob plab [5-8]. Cov kab mob hauv plab tuaj yeem tshwm sim los ntawm ntau yam kab mob, xws li kab mob, kab mob, thiab kab mob cab. Cov kab mob tshwm sim muaj xws li rotavirus (RV) A, norovirus (NoV) GI thiab GII, adenovirus, Salmonella, Campylobacter jejuni, Shigella, thiab Escherichia coli (E. coli) [2,9]. Kev sib koom ua ke ntawm cov kab mob no feem ntau ua rau muaj qhov tshwm sim hnyav dua li kev kis kab mob ib leeg [10]. Txawm hais tias cov txheej txheem ntawm kev kis kab mob ib leeg los ntawm cov kab mob no tau kawm ntau, tsis tshua paub txog cov txheej txheem tswj hwm ntawm kev sib kis ntawm lawv [11]. Kev mob raws plab tshwm sim los ntawm kab mob thiab kab mob sib kis yog ib qho teeb meem kev noj qab haus huv tseem ceeb hauv cov teb chaws tsim [12]. Kev nkag siab txog cov txheej txheem ntawm kev sib koom ua ke yog qhov tseem ceeb rau kev txhim kho cov tswv yim tswj kab mob ntau dua. Arpit Kumar Shrivastava et al. tau ua cov tshuaj tiv thaiv kab mob ntawm cov quav ntawm 130 tus menyuam yaus uas muaj mob raws plab los ntawm chaw kho mob menyuam yaus hauv Is Nrias teb thiab pom tias cov kab mob pathogenic feem ntau yog E. coli (30.07%), tom qab ntawd yog RV (26.15%), Shigella (23.84%), adenovirus ( 4.61%), Cryptosporidium (3.07%), thiab Giardia flagellates (0.77%), thiab 44 ntawm 130 tus neeg mob (33.84%) tau kis ob lossis ntau tus kab mob ib txhij [4]. Shilu Mathew et al. kuaj cov kab mob ntawm 70 tus menyuam yaus uas muaj mob plab, thiab muaj ntau qhov sib txawv ntawm cov kab mob sib xyaw thiab cov kab mob sib xyaw, suav nrog RV, NoV, Enteroaggregative E. coli (EAEC), thiab Enteropathogenic E. coli (EPEC). Piv rau cov kab mob RV thiab NoV ib leeg, EPEC thiab EAEC cov kab mob sib kis ua rau mob plab thiab ntuav ntau dua [13].

cistanche ntxiv cov txiaj ntsig-kho cem quav

Cov kab mob sib kis ua rau muaj kev hloov pauv hauv plab hnyuv ntau ntxiv, txo cov plab hnyuv microbial ntau haiv neeg, thiab nce cov kab mob hauv plab hnyuv loj [14,15], xws li ua tiav nrog ntau dua ntawm Clostridiaceae thiab Streptococaceae hauv plab, microbiota tuaj yeem cuam tshuam ncaj qha rau ntawm cov hlwb. coj mus rau ib tug series ntawm cov txheej xwm nyob rau hauv tus txheej txheem ntawm inflammatory [13]. Nyob rau hauv sib piv, Sabrina J. Moyo et al. soj ntsuam cov quav hauv plab los ntawm 723 cov menyuam yaus uas muaj mob raws plab hauv Tanzania thiab pom tias kev sib koom ua ke feem ntau tshwm sim hauv kev mob raws plab, tab sis hais tias cov kab mob ntawm ib tus kab mob yog qee zaum txhim kho los ntawm kev sib kis thiab txo qis los ntawm lwm tus, tsis muaj kev cuam tshuam ntawm kev sib kis-rau- qhov hnyav ntawm raws plab [16]. Qhov no txawv ntawm qhov kev nkag siab uas feem ntau nkag siab tias cov kab mob ntau dua, qhov kis mob hnyav dua, qhia tias muaj qee qhov tseem tsis tau piav qhia txog kev tswj hwm kev sib koom ua ke. Lub plab harbors qhov loj tshaj plaws mucosal nto thiab ua raws li qhov loj tshaj plaws tiv thaiv kab mob ntawm tib neeg lub cev. Lub plab yog raug rau ib puag ncig nyuaj nyob rau hauv uas nws yog txuas mus rau stimuli los ntawm ntau txawv teb chaws antigens [17,18]. Lub cev tsis muaj zog lossis tsis muaj kev tiv thaiv kab mob hauv lub plab yog peb lub cev thawj kab ntawm kev tiv thaiv thiab muaj lub cev tiv thaiv kab mob thiab lwm yam kev tiv thaiv kab mob. Lub cev tiv thaiv kab mob hauv lub cev muaj ntau hom kab mob ntawm tes, suav nrog cov kab mob hauv plab hnyuv epithelial (IECs) [19], mononuclear macrophages, dendritic cells, natural killer cells, mast cells, granulocytes, M cells, thiab lwm yam. Cov tshuaj tiv thaiv kab mob, xws li mucin, secretory immunoglobulin A (sIgA), thiab defensins [20]. IECs, mononuclear phagocytes, thiab cov ntaub so ntswg lymphoid ua lub luag haujlwm tseem ceeb hauv kev nkag siab cov ntsiab lus ntawm lub plab microbiome thiab hauv kev tswj lub cev tiv thaiv kab mob [21]. Ntxiv rau qhov no, muaj cov pov thawj loj hlob uas cov paj hlwb thiab cov paj hlwb, nrog rau cov neuropeptides, hloov cov kab mob hauv plab hnyuv thiab yog li cov txheej txheem hauv plab hnyuv [22]. Lub paj hlwb enteric (ENS) muaj qhov dav dav rau lwm yam kabmob ntawm lub cev, suav nrog lub hauv nruab nrab lub paj hlwb, los ntawm kev txhais cov tshuaj lom neeg cov cim los ntawm ib puag ncig rau hauv neuronal impulses los tswj thiab koom ua ke tag nrho lub cev ua haujlwm. Nws tsim ib qho kev sib txuas sib txuas ntawm enteric neuroimmunity rau kev nkag siab thiab teb rau dynamic ecosystem ntawm txoj hnyuv [23]. Thaum stimulation, lub plab kuaj pom (lossis lees paub) cov kab mob sib txuas nrog cov qauv molecules (PAMPs) thiab kev puas tsuaj cuam tshuam nrog cov qauv molecules (DAMPs) los ntawm qee cov txheej txheem sib txawv [24], regulating downstream gene transcription and inflammatory responses [25]. Cov kev tshawb fawb tsis ntev los no ntawm kev sib cuam tshuam ntawm cov kab mob-cov kab mob tau pom tias eukaryotic virus-cov kab mob sib cuam tshuam tuaj yeem nthuav dav thiab muaj kev cuam tshuam loj rau microbial pathogenesis, lav kev tshawb nrhiav ntxiv [10]. Kev sib cuam tshuam ntawm cov kab mob sib kis hauv tus tswv tsev tuaj yeem hloov cov kab mob sib kis, thiab lawv cov teebmeem feem ntau yog nyob ntawm qhov kev txiav txim ntawm cov kab mob tuaj txog hauv tus tswv tsev (intra-host nyiam cuam tshuam) [26]. Kev tshawb fawb soj ntsuam thiab kev tshawb fawb ntawm cov kab mob thiab kab mob sib kis nyob rau hauv cov pa epithelium tau rov hais dua. Muaj ntau tshaj tawm cov ntaub ntawv kho mob ntawm kev sib koom ua ke hauv plab hnyuv epithelium, tab sis kev tshawb fawb ntawm kev sib cuam tshuam mechanisms tseem nyob rau hauv thawj theem [27]. Hauv qhov kev tshuaj xyuas no, peb tau tham txog cov xwm txheej sib txawv ntawm cov kab mob thiab cov kab mob sib kis hauv cov hnyuv thiab qhov cuam tshuam ntawm kev sib koom ua ke ntawm kev tiv thaiv kab mob hauv lub cev, thiab tseem tau sau cov ntsiab lus tam sim no paub txog cov txheej txheem molecular thiab tam sim no cov teeb meem tseem ceeb hauv kev sib koom ua ke nrog cov hnyuv. kab mob uas yuav muab tswv yim tshiab rau kev tshawb fawb yav tom ntej.

cistanche tshuaj ntsuab- Kho cem quav

2. Tus "Killers" tiag tiag yog kab mob los yog kab mob? Kev Txiav Txim ntawm Kab Mob yog qhov tseem ceeb

Kev tshawb fawb thawj zaug ntawm cov kab mob-viral co-infection pib nrog "Spanish Flu", qhov twg 95% ntawm cov neeg tuag tau raug ntaus nqi los ntawm kev sib kis los ntawm Streptococcus pneumonia thiab Staphylococcus aureus. Cov kws tshawb fawb yav dhau los ntseeg tias qhov no yog ib qho kev sib piv ncaj nraim rau txoj hauv kev uas cov kab mob nyob hauv ib txwm muaj, xws li Staphylococcus aureus, coj kom zoo dua ntawm kev tiv thaiv txo qis los ntawm kev kis tus kab mob thawj zaug los ua cov kab mob. Txawm li cas los xij, qhov no yog over-simplistic; thaum kev sib koom ua ke feem ntau txhim kho thiab ua kom ntev cov tsos mob, nws tuaj yeem txo lawv hauv qee kis [28]. Txawm hais tias tus mob no muaj nyob rau hauv kev sib koom ua ke nrog cov kab mob ua pa, nws kuj tseem muaj nyob rau hauv cov xwm txheej zoo sib xws hauv kev sib koom ua ke hauv plab.

2.1. Kev kis kab mob ua raws li kab mob / kab mob hem

Thaum cov kab mob hauv plab hnyuv raug cuam tshuam los ntawm cov kab mob, lub xeev ntawm cov cell membranes cuam tshuam thiab kev tiv thaiv kev tiv thaiv kab mob ua rau muaj kev cuam tshuam rau cov kab mob hauv cov hnyuv; Txawm li cas los xij, thaum txoj hnyuv tsis tshua muaj kev kis kab mob los ntawm cov kab mob pathogenic thiab nyob rau hauv lub xeev tiv thaiv, qee cov kab mob tuaj yeem ua rau lub cev tsis muaj zog ntawm txoj hnyuv. Hauv seem no, peb piav qhia txog qhov sib txawv ntawm cov kab mob sib kis tom qab kis kab mob enteroviral.

2.1.1. Tus kab mob kis thawj zaug thiab txhawb kev kis kab mob

Kev hloov pauv ntawm tes raug ntxias los ntawm cov kab mob uas ib txwm nyob hauv lub plab tuaj yeem hloov kho lub peev xwm ntawm lwm yam kab mob (xws li, kab mob lossis kab mob) kom ua raws thiab cuam tshuam cov hlwb epithelial thiab tuaj yeem tsim lossis nyiam cov kab mob hnyav dua rau tib neeg. Txoj hauv kev uas cov kab mob sib koom ua ke ntawm cov kab mob muaj xws li ib tus neeg lossis cov txheej txheem sib xyaw ua ke, xws li kev tswj hwm ntawm cov cellular receptors, cuam tshuam ntawm epithelial teeb meem, thiab kev tawm tsam ntawm lub cev tsis muaj zog [29,30]. Transmissible gastroenteritis virus (TGEV) yog tus kab mob coronavirus uas tshwm sim los ntawm kev mob raws plab thiab mob hnyav, thiab kev kis tus kab mob TGEV tsis tu ncua ua rau lub plab hnyuv epithelial-mesenchymal hloov (EMT), piv txwv li, hloov cellular los ntawm cov hlwb epithelial mus rau mesenchymal hlwb txhawb kev txav mus los thiab cuam tshuam thiab txhim kho cov aoccuses. ntsej muag (E. facials) thiab enterotoxigenic E. coli (ETEC) K88 rau hlwb [31]. Cov kab mob pathogenic ua ntej khi rau cov kab mob receptor fibronectin los ntawm Zipper mechanism thiab txuas ntxiv mus rau daim nyias nyias protein integrin 5 txhawm rau txhawm rau ntawm tes. Nws kuj cuam tshuam tus tswv tsev los ntawm qhov sib txawv ntawm tes. Reversal ntawm EMT downregulates qhov kev qhia ntawm integrin 5 thiab fibronectin thiab inhibits adhesion ntawm ETEC K88 rau IECs (Daim duab 1A) [7,31]. RVs yog ob-stranded RNA kab mob uas yog tsev neeg Reoviridae thiab kis rau cov hnyuv me los ntawm txoj kev ntawm qhov ncauj. Nyob rau hauv tib neeg txoj hnyuv adenocarcinoma cell qauv, RV kab mob ua rau Caco{11}} cov hlwb ntau dua rau Yersinia pestis thiab Yersinia pseudotuberculosis nyob rau hauv cov hnyuv me los ntawm kev ntxiv dag zog rau cov kab mob-hlwb kev sib cuam tshuam thiab internalization. Lub intracellular proliferation ntawm cov kab mob ua rau intracytoplasmic organelle puas, ua rau txo tus kab mob antigen synthesis nyob rau hauv nruab nrab ntawm kev sib koom ua ke [32]. Aeromonas yog ib pawg ntawm Gram-negative luv luv rods ntawm tsev neeg Vibrionaceae, uas yog cov kab mob tseem ceeb ntawm cov ntses thiab qee zaus ua rau raws plab thiab kab mob hauv plab hauv tib neeg thiab tsiaj txhu [33]. Kev kis kab mob ua ntej ntawm Caco-2 hlwb nrog RV tuaj yeem cuam tshuam rau kev ua raws ntawm qee hom Aeromonas los tuav cov hlwb, thiab cov nyhuv no txawv nrog lub sijhawm ntawm kev kis kab mob (Daim duab 1A) [34]. Listeria monocytogenes (L. monocytogenes) yog kab mob Gram-zoo thiab cov kauj ruam tseem ceeb hauv nws cov kab mob yog qhov ntxeem tau ntawm cov kab mob no mus rau hauv IECs [35]. Kev sib koom ua ke ntawm RV lossis poliovirus (PV) thiab L. monocytogenes tau tshawb xyuas hauv Caco-2 cov hlwb, qhov chaw uas muaj cov kab mob RV tau nthuav tawm kev txhim kho sab hauv ntawm L. monocytogenes thiab txhawb nqa cov kab mob rov ua dua, thaum PV kab mob tsuas muaj ib qho Kev cuam tshuam me ntsis ntawm cov kab mob nkag mus ua ntej kis kab mob, cuam tshuam cov kab mob loj hlob mus rau qee qhov (Daim duab 1A) [36].

Daim duab 1. Kab mob thiab kab mob sib kis hauv txoj hnyuv. (A) Cov kab mob txhawb kev kis kab mob;

2.1.2. Tus kab mob kis thawj zaug thiab inhibits kab mob

Thaum kis tus kab mob, tus tswv tsev lub cev tiv thaiv kab mob teb rau cov stimulation ntawm cov kab mob tam sim ntawd; nws tuaj yeem txwv cov kab mob pathogenic thiab tom qab ntawd, ua rau cov cim tsim nyog los qhib lub cev tiv thaiv kab mob kom tshem tawm cov kab mob sib kis. Nyob rau hauv sib piv, thaum lub immunosuppressive chav kawm ntawv ntawm cov kab mob thawj colonizes lub plab, nws suppresses tus tswv tsev tiv thaiv kab mob thiab ua rau kom yooj yim colonization ntawm cov kab mob [37]. Piv txwv li, enterovirus 71, uas tuaj yeem pib colonize txoj hnyuv thiab ua rau cov kab mob hauv lub cev, ua kom lub cev tsis muaj zog thiab tiv thaiv kab mob los ntawm lwm cov kab mob tom qab [37,38].

Barton et al. qhia tias nas latently kis tus nas gamma-herpesvirus 68 los yog nas cytomegalovirus muaj inhibitory cuam tshuam rau L. monocytogenes [39]. Cov nyhuv inhibitory yog nyob ntawm kev ua kom lub cev ntawm macrophages thiab tsim cov cytokines hauv lub hauv paus ntawm lub cev tiv thaiv kab mob, suav nrog kev tsim cov cytokine interferon-. Raws li cov txiaj ntsig no, nws tuaj yeem ua pov thawj tias kev kis tus kab mob latent los ntawm cov kab mob kho tus tswv tsev mus rau hom kev tiv thaiv kab mob thiab npaj tus tswv tsev los tawm tsam kev sib tw ntawm cov kab mob [39,40]. Astroviruses tseem tuaj yeem ua raws li lub luag haujlwm ntawm microbiota los teeb tsa lub cev tiv thaiv kab mob thiab tiv thaiv cov kab mob hauv plab hnyuv los ntawm inducing hom III IFN qhia hauv IECs [41]. Nov kab mob tuaj yeem ua lub luag haujlwm tiv thaiv hauv DSS-induced plab hnyuv raug mob thiab murine Citrobacter-induced plab hnyuv kab mob los ntawm inducing ib qho IFN-I ( / ) teb nyob rau hauv nas nyuv thiab txhawb Interleukin 22 (IL-22) ntau lawm los ntawm natural lymphocytes (Daim duab 1B) [42].

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

2.1.3. Tus kab mob kis thawj zaug thiab nws qhov kev rov ua dua raug cuam tshuam los ntawm cov kab mob tom qab kis

Interestingly, qhov kev txiav txim ntawm tus kab mob tsis ua raws li tus kab mob kev txiav txim ntawm microorganisms. Qee qhov xwm txheej, nws tsis yog tsuas yog tus qub uas cuam tshuam rau tom kawg hauv kev sib koom ua ke, tab sis tom kawg kuj tuaj yeem ua rau ib qho uas colonizes ua ntej. Thaum ntxov li 1996, F. Superti li al. pom tias co-incubation nrog L. monocytogenes ntawm 37 ◦C rau 5 h ua rau muaj kev nce hauv RV antigen synthesis, tab sis nws tsis cuam tshuam rau PV replication hauv Caco-2 hlwb [36]. Tsab ntawv xov xwm no tau qhia tias kev kis kab mob ntawm cov cell zoo li enterocytes los ntawm cov kab mob enteroviruses sib txawv tuaj yeem cuam tshuam rau kev cuam tshuam ntawm cov hlwb mus rau cov kab mob thib ob, tab sis cov txheej txheem tsis tau tshawb pom qhov tob. Nov thiab Salmonella yog cov kab mob loj uas cuam tshuam rau tib neeg kev noj qab haus huv kev nyab xeeb. Murine NoV (MNV) activates caspase-mediated apoptotic pathways uas tua cov tswv tsev cell thiab tsim kom muaj kev sib kis [43]. Salmonella yog ib qho kab mob uas kis tau los ntawm cov kab mob hauv lub cev, tiv thaiv kev tuag ntawm tes thiab ua kom cov cell ciaj sia, yog li tsim kom muaj kab mob mus ntev hauv cov tswv tsev [44]. Kab mob ntawm RAW 264.7 hlwb los ntawm nas NoV ua rau apoptosis thiab nce replication ntawm Salmonella Heidelberg los ntawm cleavage ntawm poly ADP ribose polymerase (PARP), caspases 3 thiab 9 [43,45]. Txawm li cas los xij, kev kis tus kab mob Salmonella Heidelberg thaiv cov txheej txheem apoptotic los ntawm MNV, thiab qhov no yuav cuam tshuam nrog kev ua kom PI3K / Akt txoj hauv kev raug ntxias los ntawm hom III secretion system effector SopB (Daim duab 1C) [45].

2.2. Cov kab mob kab mob ua raws li kab mob

Kev sib cuam tshuam ntawm cov kab mob thiab cov kab mob ua lub luag haujlwm tseem ceeb ntawm tus tswv tsev-cov kab mob sib txuas. Zoo ib yam li 2.1, kab mob kab mob muaj ob qhov cuam tshuam rau kev kis kab mob tom ntej. Ntawm ib sab, cov kab mob enteric kuj tuaj yeem pab ntau yam enteroviruses hauv kev kis kab mob, piv txwv li, ntau cov kab mob enteric txhim kho PV miscibility efficiency thiab kev noj qab haus huv los ntawm kev txhawb nqa cov kab mob DNA recombination [46]; Qee cov polysaccharides thiab lipids nyob rau saum npoo ntawm cov kab mob enteric tuaj yeem txhim kho thermal stability ntawm qee cov kab mob enteric [10]. Ntawm qhov tod tes, cov kab mob enteric tuaj yeem cuam tshuam cov kab mob kis, xws li Salmonella inhibits Nov replication hauv nas macrophages [45]; bacteriocin CRL35 (ECRL) secreted los ntawm E. fecalis inhibits synthesis ntawm viral glycoproteins tsim nyog rau kis kab mob thiab replication [47]; Lub xub ntiag ntawm micro bacteriocins nrog cov tshuaj tiv thaiv kab mob hauv cov kab mob supernatants txo cov kab mob titers hauv vitro [48].

2.2.1. Cov kab mob kis kab mob ua ntej thiab txhawb kev kis kab mob

Cov microbiota txhim kho qhov kev rov ua dua thiab sib kis ntawm enteroviruses los ntawm ntau lub tshuab. Peb feem ntau nkag siab tias cov kab mob tuaj yeem tiv thaiv lub cev tiv thaiv kab mob los tiv thaiv kab mob los ntawm kev tshem tawm [46,49]. Kev sib txuas ncaj qha ntawm cov kab mob saum npoo polysaccharides tuaj yeem txhim kho kev ruaj ntseg ntawm enteric virions thiab ua kom cov kab mob txuas mus rau tus tswv tsev receptors [50].

Qee hom kab mob ua rau muaj kab mob sib kis ntawm cov kab mob mammalian. Cov kab mob sib kis kab mob sib kis kab mob sib kis nrog cov kab mob ua rau cov hlwb [50]. Cov kab mob RNA xws li PV, enteroviruses, thiab NoVs muaj xws li cov kab mob sib txawv ntawm cov kab mob sib txawv nrog cov kev hloov pauv sib txawv, thiab kev hloov pauv hauv lawv cov RNAs thaum rov ua dua tuaj yeem ua rau muaj txiaj ntsig zoo [51]. Nws tau pom tias enteric PV khi ncaj qha rau ntau yam kab mob, yog li txhawb kev muaj zog ntawm cov kab mob ntawm cov kab mob hauv lub cev thiab kho cov kab mob sib kis tau zoo dua. Qhov tseem ceeb, cov kab mob kab mob cuam tshuam nrog cov kab mob ua rau muaj kev sib koom ua ke ua rau muaj kev txhawb nqa caj ces rov ua dua ntawm ob tus kab mob sib txawv, yog li tshem tawm cov kev hloov pauv tsis zoo, rov ua kom cov kab mob kis tau zoo, thiab tsim cov progeny nrog lub peev xwm loj hlob nyob rau hauv lwm yam kev txwv (Daim duab 1D) [46] . Enteroviruses tuaj yeem khi rau cov kab mob ntawm cov kab mob ntawm cov kab mob polysaccharides. Cov ntaub so ntswg cov ntshav antigens (HBGAs) qhia nyob rau hauv plab hnyuv epithelium yog xav tias yog receptors los yog co-receptors rau tib neeg NoVs (HuNoVs) [52]. HuNoVs cuam tshuam nrog HBGAs glycan thiab khi rau cov kab mob tshwj xeeb [53]. Kev khi ntawm enteroviruses rau cov kab mob hauv lub hnab ntawv kuj tseem txhim kho lawv cov thermal stability (Daim duab 1D) [54]. Kev khi ncaj nraim ntawm cov kab mob ntawm cov kab mob polysaccharides txhim kho kev ruaj ntseg ntawm cov kab mob enterovirus thiab ua rau kom cov kab mob txuas ntxiv mus rau host receptors. Sharon K. Kuss et al. pom tias qhov muaj peev xwm ntawm PV tau nce zuj zus tom qab incubation nrog Gram-negative (E. coli) lossis Gram-positive (Bacillus cereus (B. cereus), E. facials) kab mob. Kev raug rau B. cereus ua rau muaj zog adhesion ntawm PV rau Hela hlwb thiab nce kis tau los ntawm ntau tshaj 500% [55]. Cov kev tshawb fawb ntxiv tau qhia tias cov kab mob-lipopolysaccharide (LPS), peptidoglycan (PG), thiab lwm yam N-acetylglucosamine uas muaj polysaccharides nce PV khi rau nws cov receptors thiab cov kab mob tua (Daim duab 1D) [55]. Nws ua raws li kev khi rau cov kab mob ua kom muaj kev ruaj ntseg ntawm cov kab mob plhaub raug rau qhov kub thiab txias thiab txhawb kev hloov ntawm ib puag ncig ntawm enteroviruses [56].

Cov teebmeem ntawm cistancetubulosa- Kho cem quav

2.2.2. Kab mob Inhibit Viral Infections

Thaum lub sij hawm tus txheej txheem ntawm NoV thiab Salmonella co-kab mob, nws tau pom tias Salmonella enterica pre-kis kab mob ntawm RAW 264.7 hlwb txo NoV replication nyob rau hauv nas los ntawm kev thaiv kab mob binding rau macrophages thaum ntxov nyob rau hauv lub viral lub neej voj voog thiab inducing zus tau tej cov tshuaj tiv thaiv cytokines xws li IL-6, IFN- , TNF- tom qab [11,45,57]. Ntxiv nrog rau cov kab mob nyob, qee cov kab mob tau pom tias ua rau muaj kev tiv thaiv kab mob hauv lub cev los ntawm kev hu xov tooj zoo li receptors (TLRs). Hom 1 pilus adhesin FimH-induced innate antiviral immunity yog txuam nrog IFN- ntau lawm thiab yuav tsum muaj kev koom tes ntawm MyD88, Trif, TLR4, IRF-3, thiab hom I IFN signaling (Daim duab 1C) [58]. Cov kab mob flagellin, ib qho tseem ceeb ntawm cov kab mob flagellum, tuaj yeem ua kom muaj kev tiv thaiv kab mob zoo hauv IECs, uas yog suav tias yog lub cev tiv thaiv kab mob loj hauv plab thiab siv los ua cov tshuaj tiv thaiv hauv kev txhim kho ntau yam tshuaj tiv thaiv [59,60]. Zhang et al. qhia tias kev kho mob ntawm tus qauv nas nrog cov kab mob flagellin tuaj yeem tiv thaiv thiab kho tus kab mob RV. Qhov kev tiv thaiv no tuaj yeem txuas ntxiv mus rau lwm yam kab mob enterovirus, suav nrog tus kab mob eutherian [61]. Qhov induction ntawm cov tshuaj tiv thaiv kab mob los ntawm flagellin yog nyob ntawm qhov ua kom zoo li Tus Hu Xov Tooj 5 (TLR{24}}) thiab NOD-zoo li receptor C4 (NLRC-4) ntawm dendritic cell nto thiab inductions ntawm downstream. cytokines IL-22 thiab IL-18 [62]. Kev sib xyaw ua ke ntawm IL-18-induced apoptosis thiab IL-22-induced proliferation tau ua rau muaj kev hloov pauv sai ntawm villi epithelial hlwb dua li tus nqi ntawm cov kab mob ntawm cov hlwb tshiab (Daim duab 1C) [61].

2.3. Mechanisms ntawm Synergism lossis antagonism ntawm Enteric Pathogens

Nws tau dhau los ua qhov pom tseeb tias kev sib txuas lus sib txuas lus thiab kev sib cuam tshuam ntawm cov kab mob thiab cov kab mob ua lub luag haujlwm tseem ceeb ntawm tus tswv tsev-cov kab mob sib txuas [50]. Feem ntau, cov txiaj ntsig ntawm kev sib koom ua ke nrog cov kab mob enteric yog muab faib ua ob yam tseem ceeb: thawj zaug, kev sib cuam tshuam ncaj qha ntawm cov kab mob, xws li kev sib txuas ntawm cov kab mob ntawm cov kab mob polysaccharides rau cov kab mob kis, txhim kho lawv cov thermal stability [54,56]. Qhov thib ob, hauv kev ua tsis ncaj, tus tswv tsev cov hnyuv cuam tshuam los ntawm cov kab mob pathogen thiab nkag mus rau "kev cuam tshuam" lub xeev muaj kev cuam tshuam los ntawm lwm cov kab mob, xws li kev puas tsuaj hauv plab hnyuv, plab hnyuv tsis zoo, thiab kev txhim kho ntawm cov cell nto receptor qhia [63], thiab lwm yam (Daim duab 1E). Kev tawm tsam ntawm cov kab mob kuj tseem muaj, suav nrog, tab sis tsis txwv rau kev sib tw noj zaub mov ntawm cov kab mob sib txawv [64]; secretions ntawm tej yam kab mob inhibit qhov synthesis ntawm tseem ceeb viral proteins; thawj tus kab mob ua rau lub cev tsis muaj zog tiv thaiv kab mob tom qab [39,40]; nthuav tawm lub cev tiv thaiv kab mob los yog txhawb nqa tus tswv kom tso cov tshuaj uas tsis muaj teeb meem rau nws tus kheej tab sis inhibits kev kis tus kab mob tom kawg, xws li interferons, bacteriocins, antimicrobial peptides nrog cov tshuaj tua kab mob, thiab lwm yam. (Daim duab 1E) [29,57] .

3. Kev cuam tshuam ntawm Pathogen Interactions ntawm Host Intestinal Immunity (Kev Sib Tham Zoo Tshaj Plaws ntawm Pathogen thiab Intestine)

Lub plab yog qhov loj thiab xaj tag nrho; thaum muaj kab mob, qhov nyiaj tshuav no tuaj yeem cuam tshuam. Qhov kev sib txuas ntawm cov kab mob, kab mob, thiab kev tiv thaiv kab mob hauv plab yog qhov sib txawv thiab ntau txoj kev, thiab kev sib cuam tshuam ntawm peb qhov no muaj cov txheej txheem sib txawv [65]. Qhov kev tshuaj xyuas no nthuav dav faib cov kev sib cuam tshuam thiab piav qhia cov ntsiab lus hauv tsib yam: cov kab mob hauv plab hnyuv thiab lawv cov secreted effectors, signaling, autoimmunity, noj zaub mov tsis zoo, thiab lub plab microbiome.

3.1. Cov kab mob hauv plab hnyuv thiab lawv cov khoom zais cia

Lub plab hnyuv epithelium muaj rau 6 lub luag haujlwm sib txawv ntawm cov hlwb: enterocytes, enteroendocrine hlwb, Paneth hlwb, tuft hlwb, khob hlwb, thiab microfold (M) hlwb [25]. Cov hlwb no ua lub luag haujlwm hauv kev nqus cov khoom noj, tshuaj hormone secretion, antimicrobial peptide (AMP) secretion, gustatory chemosensory teb, mucus ntau lawm, thiab antigen sampling, feem [66]. Txawm hais tias cov hlwb epithelial tsis feem ntau suav hais tias yog lub cev tiv thaiv kab mob, lawv tau teb rau cov kab mob thiab ua lub luag haujlwm tseem ceeb hauv kev tsim cov tshuaj tiv thaiv kab mob hauv plab uas siv ob qho tib si autonomous thiab involuntary mechanisms [67]. Lub kaw ntom nti ntawm tes-rau-cell junctions tsim cov kab mob hauv plab los tswj kev nkag ntawm microbiota, cov as-ham, thiab lwm yam khoom los ntawm lumen mus rau hauv lub cev [18,68]. Qee cov proteins muaj nyob rau saum npoo ntawm enterocytes uas tuaj yeem ua raws li cov receptors rau cov kab mob [68,69]. Los ntawm stimulating cov kab mob, cov enterocytes tsim cov tshuaj tua kab mob, piv txwv li, inhibiting zos kab mob los ntawm secreted yam. Tsis tas li ntawd, enterocytes tsim cytokines thiab chemokines uas tswj kev tiv thaiv kab mob thiab ua rau lub cev tiv thaiv kab mob los ntawm cov ntaub so ntswg hauv lub cev tiv thaiv kab mob [67]. Cov kab mob thiab cov kab mob hauv cov kab mob hauv lub cev (IBPs) cuam tshuam cov kab mob monocytes / macrophages (MOs / MPs) thiab dendritic cells, epithelial cells, fibroblasts, thiab endothelial hlwb ntawm txoj hnyuv. Txawm li cas los xij, cov hlwb sib txawv thaum kawg no tseem nyob hauv lub xeev metabolic quiescent thaum lub sij hawm kis kab mob thiab tsis tuaj yeem ua kom muaj txiaj ntsig zoo ntawm cov kab mob thiab IBPs. Cov kab mob thiab IBPs tuaj yeem rov tsim kho cov cell metabolism hauv cov kab mob tshwj xeeb kom nce cov khoom noj khoom haus, lub zog, thiab cov metabolites uas xav tau cov kab mob kom tso cai rov ua dua [70]. Nyob rau hauv luv luv, cov kab mob feem ntau tswj hwm tus tswv tsev cell metabolism los ntawm "pro-viral metabolic hloov" los ua kom zoo dua cov kev cai biosynthetic ntawm tus kab mob. Tsis tas li ntawd, cov tswv tsev cell tau tsim cov tswv yim metabolic los tiv thaiv tus kab mob sib kis los ntawm "kev hloov pauv metabolic" [70,71]. Tuft hlwb yog chemosensory hlwb txuam nrog plab hnyuv tiv thaiv los ntawm kev tsim cov cytokines xws li IL-25 [72]. CD300lf yog MNV receptor. Cluster cells tau pom tias yog hom tsis tshua muaj IEC uas nthuav qhia CD300lf thiab yog lub hom phiaj hlwb ntawm nas plab hnyuv MNV. Hom 2 cytokines uas txhawb kev loj hlob ntawm pawg hlwb tau pom los txhawb MNV kab mob hauv vivo. Cov cytokines no tuaj yeem hloov pauv rau lub luag haujlwm ntawm commensal flora hauv kev txhawb nqa tus kabmob kis [73]. Epithelial microfold (M) cov hlwb nyob hauv cov follicle-associated epithelium thiab tuaj yeem kuaj ntau yam khoom, xws li soluble antigens thiab microorganisms, los ntawm cov dej-theem cytosolic haus thiab receptor-mediated endocytosis [74]. M cell-dependent antigen uptake yog kho kom haum xeeb, tsawg kawg hauv ib feem, los ntawm cov receptors tshwj xeeb, xws li 1-integrins, cellular prion proteins, thiab glycoprotein-2 (GP2). GP2-dependent bacterial uptake pib antigen-specific secretion ntawm M cells thiab tuaj yeem tswj cov kab mob hauv plab hnyuv homeostasis los ntawm kev kho cov kab mob cellular [75]. M cell-dependent antigen thauj txhawb nqa lub cev tiv thaiv kab mob tiv thaiv kab mob hauv plab hnyuv kom txo tau cov kab mob kab mob uas ua rau cov kab mob colitis hauv nas [76]. Txawm li cas los xij, ntau yam kab mob hauv plab, xws li Shigella, Yersinia pestis, Brucella abortus, eutherian tus kab mob, thiab khaus prion protein, siv M cell ua lub portal rau thawj zaug ntxeem tau [74]. Raws li, M cell-dependent antigen uptake muaj ob qho tib si muaj txiaj ntsig thiab ua rau muaj kev puas tsuaj hauv lub cev ntawm cov kab mob mucosal thiab tus tswv tsev tiv thaiv (Daim duab 2).

Daim duab 2. Kev sib tw scenario ntawm cov kab mob thiab kab mob sib kis thiab lawv cov txiaj ntsig ntawm kev tiv thaiv tus tswv tsev

Paneth hlwb yog cov IEC tshwj xeeb uas txwv cov kab mob nkag los ntawm kev zais cov tshuaj tiv thaiv kab mob, suav nrog lysozyme [77,78]. Cov kab mob pathogenic tuaj yeem cuam tshuam rau Golgi apparatus, ua rau endoplasmic reticulum (ER) kev ntxhov siab, cuam tshuam nrog protein secretion, thiab inhibit antimicrobial protein xa, yog li inhibiting antimicrobial tiv thaiv hauv txoj hnyuv. Thaum kis kab mob, lysozyme tuaj yeem zais los ntawm secretory autophagy (ib txoj hauv kev autophagy-based secretory pathway), yog li hla txoj kev zais cia ib txwm muaj; Cov kab mob-induced endoplasmic reticulum kev nyuaj siab ua rau secretory autophagy nyob rau hauv Paneth hlwb, yuav tsum tau exogenous signals los ntawm haiv neeg lub cev tiv thaiv kab mob [77]. AMPs yog ib chav loj ntawm me me, feem ntau zoo them polypeptides uas tawm tsam cov cell membranes ntawm cov kab mob, fungi, thiab lwm yam kab mob [67]. Mammalian Paneth hlwb yog cov tsim tawm AMP tseem ceeb hauv txoj hnyuv. Tus kab mob Salmonella ua rau muaj ntau ntxiv ntawm Paneth hlwb thiab IECs thiab feem ntau ua rau cov kev pab cuam antimicrobial [79]. Paneth cells tuaj yeem cuam tshuam ncaj qha rau lub plab microbiota lossis qhov tshwm sim ntawm tus kab mob kis los ntawm kev tswj hwm cov kab mob. Paneth hlwb tseem ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv tus tswv los ntawm kev hnov ​​​​cov kab mob los ntawm TLRs [78]. Yog li, Paneth hlwb ua lub luag haujlwm tseem ceeb hauv kev tsim cov microbiome thiab kev tiv thaiv tus tswv. Hom III tej yam ntuj tso lymphocytes (ILC3s) muaj nyob rau hauv cov qog nqaij hlav hauv nruab nrog cev thiab cov hnyuv thiab yuav tsum tau tiv thaiv cov kab mob hauv plab hnyuv. G protein-coupled receptor 183 (GPR183) yog chemotactic receptor qhia ntawm ILC3 hauv cov nas thiab tib neeg. Hauv vivo, GPR183 deficiency ua rau muaj kev faib tawm tsis zoo ntawm ILC3 hauv cov qog nqaij hlav mesenteric thiab txo qis ILC3 tsub zuj zuj hauv cov hnyuv, thiab yog li GPR183- cov nas tsis muaj peev xwm kis tau los ntawm cov kab mob hauv plab hnyuv ntau dua [80]. Tsis tas li ntawd, ILC3 qhia txog vasoactive plab hnyuv peptide (VIP) receptor 2 (VPAC2), thiab VIP tau txheeb xyuas los txhim kho kev tiv thaiv kab mob murine Citrobacter los ntawm kev txhawb nqa CCR9 qhia ntawm ILC3 thiab kev ua haujlwm hauv plab hnyuv [81]. Salmonella Typhimurium (STM) yog ib qho kab mob hauv plab hnyuv uas ua rau mob, thiab tom qab ntawd cov kab mob rov ua dua cov txheej txheem metabolic thiab tiv thaiv kab mob ntawm cov hnyuv, yog li txhawb nqa STm expansion [82]. Lub plab hnyuv mucosa zais cov tshuaj tiv thaiv kab mob peptides rau hauv plab hnyuv lumen, suav nrog cov tshuaj tua kab mob lectin RegIII [83] thiab cov kab mob tshiab bactericidal protein SPRR2A (me me proline-nplua nuj protein 2A) [84]. RegIII txhim kho mucosal o los ntawm kev nce qib ntawm TNF- thiab IL-6 cytokines, Kc thiab Mpi2 chemokines, thiab lipocalin-2, hauv murine. Cov theem mob ntawm STm kab mob txhawb nqa txoj hnyuv plab hnyuv ntawm STm [83]. RegIII kuj tau hloov kho qhov muaj pes tsawg leeg ntawm cov nroj tsuag commensal thaum lub sij hawm kis kab mob, txo qhov kev faib ua feem ntawm anaphylactic bacilli. Qhov no ua rau nws ua kom ntev lub neej tsis tu ncua ntawm cov kab mob pathogenic nrog rau lub sijhawm ntawm enteropathy thaum muaj kab mob, thaum ntxiv nrog cov tshuaj lom neeg tshwj xeeb lossis vitamin B6 ua rau kom tshem tawm cov kab mob hauv plab hnyuv thiab txo cov enteropathy [83]. Cov kab mob bactericidal tshiab SPRR2A (me me proline-nplua nuj protein ntau 2A) txawv ntawm cov paub txog flora-induced AMP nyob rau hauv nws phylogeny thiab mechanism ntawm kev txiav txim, yog induced los ntawm anti-parasitic hom 2 kev tiv thaiv, thiab xaiv inhibits Gram-zoo commensal thiab pathogenic cov kab mob, tiv thaiv kab mob plab hnyuv tiv thaiv kab mob ntxeem tau thaum lub plab hnyuv kab mob helminth [84]. Interferons yog tsim los ntawm lymphocytes. Hom I (IFN- / ) thiab hom III (IFN-λ1-4) IFNs siv cov tshuaj tiv thaiv kab mob sib xyaw ua ke ntawm cov hlwb los ntawm inducing the transcription of 175,000 of antiviral IFN-stimulated genes (ISGs) and promoting viral clearance [85]. Muaj cov ntaub ntawv pov thawj uas muaj ntau yam kev qhia ntawm hom I IFN tuaj yeem cuam tshuam cov tshuaj tiv thaiv kab mob tiv thaiv kab mob, thiab hauv kev kis kab mob-cov kab mob sib kis, hom I IFN tau xav tias yog qhov tseem ceeb hauv kev txhawb nqa cov kab mob thib ob. Muaj cov txheej txheem sib txawv uas paub tias cuam tshuam nrog hom I IFN, suav nrog inhibition ntawm Th17 thiab cov lus teb neutrophil; txo qis neutrophil ntau lawm, nrhiav neeg ua haujlwm, thiab muaj sia nyob; inhibition ntawm neutrophil chemotactic agents; thiab txo IL-17 ntau lawm los ntawm T cells [86]. Hom III IFNs (IFN-λ) yog nyob rau hauv nruab nrab ntawm cov cua daj cua dub ntawm tus kab mob [85]. Hom III IFNs tiv thaiv cov neeg laus thiab lactating nas los ntawm enterovirus kab mob thiab enterovirus-induced tuag [87]. Mouse RV induces IFN-l qhia thiab IL-1 ntau lawm hauv IEC, thaum IEC-derived IL-1 activates IL-22 qhia hauv plab hnyuv ILC3 cov pej xeem los ntawm lamina propria. IL-22 synergistically activates STAT1 nrog IFN-l kom txo tau tus kab mob enteric RV. Kev kho mob ua ke nrog IL-22 thiab IL-18 tiv thaiv nas los ntawm RV kab mob thiab kab mob raug mob [67]. Nov kab mob tuaj yeem ua lub luag haujlwm tiv thaiv hauv DSS-induced plab hnyuv raug mob thiab murine Citrobacter-induced plab hnyuv kab mob los ntawm eliciting ib qho IFN-I teb nyob rau hauv nas nyuv los txhawb IL-22 ntau lawm los ntawm natural lymphocytes (Daim duab 2) [42] . IFN- thiab IFN- tiv thaiv kab mob los ntawm NoV hauv cov nas, tab sis tsuas yog IFN-λ tswj cov kab mob hauv plab tsis tu ncua, qhia tias IFN-λ tshwj xeeb inhibits plab hnyuv NoV [88]. Yog li, IFN-λ ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv lub plab hnyuv mucosa los ntawm kev kis kab mob [57]. Tsis tas li ntawd, IFN-λ plays lub luag haujlwm ntawm ntau yam kab mob ntawm cov kab mob hauv nruab nrog cev thiab cov kab mob sab nraud, xws li L. monocytogenes, Streptococcus pneumoniae, Haemophilus influenza, Staphylococcus aureus, Salmonella enterica, Shigella, thiab Mycobacterium tuberculosis [89]. Piv txwv li, kab mob ntawm nas placenta los ntawm Listeria monocytogenes ua rau muaj kev tswj hwm ntawm IFN-λ2/λ3 mRNA qhia qib hauv cov placenta, qhia tias IFN-III pab txhawb kev tiv thaiv epithelial los ntawm kab mob (Daim duab 2) [90]. Cov vitamin D receptor (VDR) belongs rau tsev neeg ntawm cov receptors nuclear uas tau qhia ntau heev hauv cov hnyuv thiab cov hnyuv thiab ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv hauv zos thiab hauv lub cev, tiv thaiv tus tswv, thiab kev sib cuam tshuam ntawm tus tswv tsev-microbe [91]. VD-VDR signaling tswj cov plab hnyuv ua haujlwm los ntawm ntau lub tswv yim, xws li kev tswj hwm ntawm kev sib txuas ntawm cov protein ntau, inhibition ntawm IEC apoptosis, nce qib ntawm autophagy hauv IEC, thiab txhim kho cov mucosal kho [91]. VDR muaj kev tswj xyuas cov kab mob ntawm cov kab mob thiab kab mob hauv plab. Rong Lu et al. pom tias lysozyme tau txo qis hauv Paneth hlwb los ntawm Paneth cell-specific VDR knockout (VDR∆PC) nas, nrog txo qis cov kab mob kab mob loj hlob inhibition thiab txo autophagic teb; VDR∆PC nas tau txhim kho o tom qab kis kab mob Salmonella, thiab qhov tsis zoo ntawm lawv cov lus teb autophagic ua rau muaj kev tiv thaiv tsis muaj zog tiv thaiv kab mob cuam tshuam thiab txhawb kev mob plab hnyuv hauv nas [92]. Los ntawm kev tsim cov nas knockout nrog kev tshem tawm VDR hauv IEC (VDR∆IEC), Paneth hlwb (VDR∆PC), thiab cov hlwb myeloid (VDR∆Lyz), Jilei Zhang li al. txheeb xyuas cov kab mob thiab kab mob sib xyaw thiab cov metabolites ntawm txhua pawg nas thiab pom tias cov ntaub so ntswg tshwj xeeb tshem tawm ntawm VDR hloov cov neeg kis tus kab mob thiab ua haujlwm hloov cov kab mob receptors, uas ua rau muaj kev cuam tshuam ntawm ecological dysregulation, metabolic dysfunction, thiab kev pheej hmoo kis mob. Kev nthuav qhia ntawm TLR3 / 7, NOD1 / 2, thiab NLR6 tau hloov kho hauv cov nas nas, thiab C-hom lectin receptor 4L (CLR4L) tau nce siab (Daim duab 2) [93]. Zuag qhia tag nrho, qhov kev hloov pauv tseem ceeb hauv cov qauv lees paub receptors (PRRs) ntawm cov kab mob VDR knockout nas qhia txog kev cuam tshuam ntawm VDR ntawm txoj hnyuv homeostasis thiab PRRS qhia. Tsis muaj VDR hauv Paneth hlwb tuaj yeem ua rau muaj kab mob tsis zoo, uas tuaj yeem ua rau muaj kev cuam tshuam ntawm epithelial barrier ua haujlwm. Kev ua kom VDR muaj lub luag haujlwm tswj hwm hauv enterovirus-tus tswv kev sib cuam tshuam [91–93]. Qhov no qhia tias VDR tuaj yeem yog lub hom phiaj rau kev kawm hauv cov kab mob-viral-tus tswv kev sib cuam tshuam.

3.2. Immune and Inflammatory Signaling Pathways

Lub cev tiv thaiv kab mob hauv lub cev tswj hwm ntau yam kab mob-encoded PRRs kom paub txog PAMPs thiab DAMPs [24,94]. PRRs feem ntau yog tsim los ntawm TLRs, C-hom lectin receptors, cytoplasmic DNA sensors (ie, cyclic GMP-AMP synthases), thiab ntau lwm yam cytoplasmic receptors, xws li RIG-I-zoo li receptors lossis Nod-zoo li receptors [24,95] . Cov kab mob inflammatory vesicles yog cytoplasmic multiprotein complexes koom nrog hauv kev tiv thaiv kab mob, tseem ceeb heev rau tus tswv tsev tiv thaiv thiab kho [96]. Lawv feem ntau sib sau ua ke nrog cov nucleotide binding domains thiab leucine-nplua nuj rov ua dua (NLR) cov proteins, xws li NLRP1, NLRP3, NAIP, thiab NLRP6 [62,97]. Thaum ua kom tiav, cov proteins sensors nrhiav ua ntej caspase-1 ncaj qha lossis ncaj qha los ntawm adapters ASC lossis NLRC4, ua rau caspase-1 dimerization thiab ua kom. Tom qab ntawd, caspase-mediated processing ntawm pro-interleukin (IL)-1 , pro-IL-18, thiab cov pore-forming protein gasdermin D (GSDMD) ua rau kom loj hlob thiab tso tawm ntawm cov cytokines, thiab. raws li cellular scorching (Daim duab 2) [97]. Muaj ntau txoj kev tshawb fawb ntawm cov kab mob cuam tshuam nrog cov tswv tsev teeb liab txoj hauv kev hauv kev ua pa ntawm kev sib kis, xws li kev ua kom lub TLR2-MYD88-NLRP3 signaling axis mediating nce hauv IL-1 thaum lub sij hawm co - kis kab mob khaub thuas A thiab Streptococcus pneumoniae [98], thiab muaj cov txheej txheem zoo sib xws hauv cov hnyuv. Thaum lub sij hawm mob plab hnyuv kab mob, cov kab mob hauv lub cev hauv cov nas tau qhib thiab tsim IL-23 thiab IL-22 los txhawb kev tsim cov tshuaj tua kab mob peptide thiab tshem tawm cov kab mob. IL-36R signaling txhawb IL-23/IL-22/antimicrobial peptide thiab IL-6/IL-22/antimicrobial peptide-mediated inhibition ntawm plab hnyuv kab mob kab mob los ntawm kev sib koom ua ke hauv lub cev thiab hloov lub cev tiv thaiv kab mob (Daim duab 2) [99]. TLR3 yog tam sim no nyob rau hauv IECs, thiab nws paub tus kab mob kis thiab induces NF-κB signaling thiab IL-15 ntau lawm [67]. RV genomic dsRNA thiab nws cov synthetic analog polyinosinic polycytidylic acid (poly (I: C)) ua rau cov mucosal puas loj heev hauv cov hnyuv. Thaum khi rau TLR3, dsRNA ua rau muaj kev tso tawm ntawm IL-15 los ntawm IECs, uas cuam tshuam cov mucosal homeostasis los ntawm kev ua ntawm CD8 + IELs [100]. Lub plab hnyuv epithelial TLR3 qhia cuam tshuam nrog RV susceptibility. Viral shedding tau nce ntxiv hauv TLR3 lossis Trif-deficient nas piv rau kev tswj hauv RV kev sim kab mob, thiab kev qhia txog cov tshuaj tiv thaiv kab mob thiab cov tshuaj tiv thaiv kab mob tau txo qis (Daim duab 2) [101]. TLR3 signaling exerts ib tug dual nyhuv ntawm plab hnyuv kab mob, pab tsis tau tsuas yog rau tus tswv tsev tiv thaiv tab sis kuj mus rau kab mob pathogenesis. TLR4 yog qhia nyob rau saum npoo ntawm ntau yam phagocytic hlwb, suav nrog macrophages, peripheral ntshav monocytes, neutrophils, thiab DCs [24], hom I "hair" FimH [58] lossis LPS uas tsim los ntawm cov kab mob Gram-negative tuaj yeem txhawb nqa TLR4 thiab kho kom haum xeeb. downstream NF-κB thiab MAPK signaling pathways (Daim duab 2) [102]. TLR5 paub txog cov flagellin extracellular thiab siv MyD88 los pib MAPK signaling thiab NF-κB ua kom muaj zog cytokine secretion thiab ua rau cov lus teb inflammatory los tshem tawm cov kab mob [103]. Lub flagellin ntawm F4 ETEC induces TLR5-mediated IL-17C qhia nyob rau hauv IECs thiab tsub kom qhov kev qhia ntawm antimicrobial peptides thiab nruj hlws ris proteins nyob rau hauv ib tug autocrine/paracrine yam uas txhawb mucosal tswv tsev tiv thaiv kab mob [24,104 ]. Tsis tas li ntawd, flagellin qhib IL-22 thiab IL-18 ua kom dhau los ntawm TLR5/NLRC4 (Daim duab 2) [62], tsav IL-18-induced apoptosis ntawm tus kab mob kis nrog rau IL{{84} }induced proliferation [61], yog li inhibiting kab mob. Nws tau pom tias epithelial NAIP/NLRC4 inflammatory vesicles tsav heterogeneous cell tuag (xws li caspase-1-mediated scorch tuag thiab caspase-8/-3 mediated apoptosis) ntawm IEC kom txo cov ntaub so ntswg ntawm STm , los txhawb txoj hnyuv epithelial cell expulsion yuav txo tau STm load los ntawm kev tsav cov hnyuv epithelial cell scorch tuag los yog apoptosis thiab txhawb plab hnyuv epithelial cell exulsion, li no alleviating TNF-induced plab hnyuv epithelial barrier cuam tshuam (Daim duab 2). NAIP/NLRC4 tsis muaj peev xwm ua rau nce TNF ntau ntau, plab hnyuv epithelial teeb meem cuam tshuam, thiab cov ntaub so ntswg tsis zoo hauv cov nas [105]. NLRP6 inflammatory vesicles koom nrog hauv kev tswj hwm ntawm mucus secretion, antimicrobial peptide ntau lawm, NF-κB, MAPK, thiab IFN signaling pathways thiab ua lub luag haujlwm tseem ceeb hauv kev tiv thaiv tus tswv [106]. NLRP6 ua lub luag haujlwm hauv cov hlwb sib txawv. Hauv IECs, NLRP6 hnov ​​​​cov microbial-associated metabolites, tsim ASC-dependent inflammatory vesicles, thiab txhawb nqa downstream IL{101}} tso tawm thiab tso tawm ntawm cov tshuaj tua kab mob peptides (Daim duab 2) [96]. Hauv txoj hnyuv, NLRP6 tswj IL{105}} ntau lawm, khob ntawm tes ua haujlwm, thiab flora homeostasis thiab koom tes nrog NLRP9 hauv kev tiv thaiv kab mob [106]. Hauv khob-oocytes, NLRP6 tau pom los tswj cov hnoos qeev tso rau hauv cov hlwv thiab autophagy-dependent yam los tiv thaiv kev cuam tshuam los ntawm cov kab mob hauv plab [106,107]. Ib yam li ntawd, NLRP6 tau pom los tiv thaiv tus kab mob enterovirus, nrog rau cov kab mob ntau ntxiv hauv cov nas nas kab mob uas kis tau tus kab mob cerebral myocarditis lossis MNV hauv Nlrp6 knockout thiab tswj cov nas. NLRP6 tau pom tias inhibit enterovirus kab mob los ntawm txoj kev interferon los ntawm kev khi rau kab mob RNA ntawm RNA-decapping enzyme DHX15 [108]. Ligands xws li ob-stranded RNA (dsRNA) uas tsim los ntawm ntau cov kab mob tuaj yeem cuam tshuam nrog NLRP6 los ua kom muaj kua-kua theem sib cais (LLPS). Kev hloov pauv hauv thaj tsam zoo ntawm NLRP6 yog qhov tseem ceeb rau LLPs, uas inhibits dsRNA-induced NLRP6 chaw tsim, GSDMD cleavage, thiab cell tuag, thiab impairs anti-microbial tiv thaiv hauv nas [107]. Mammalian IECs tuaj yeem paub tus kab mob los ntawm MDA-5 thiab NLRP6 los qhib hom III IFN signaling lossis los ntawm TLR3 los qhib NF-κB signaling [67]. RVs tshwj xeeb kis tus tswv tsev me me IECs thiab tau hloov kho cov tswv yim los tawm tsam IFN thiab NF-κB txoj kev taw qhia [109]. NLRP9 tau hais tshwj xeeb hauv IECs thiab txwv tsis pub muaj tus kab mob RV [110]. NLRP9b lees paub luv luv ob-stranded RNA fragments ntawm RNA decapping enzyme Dhx9 thiab cuam tshuam nrog cov splice proteins ASC thiab caspase-1 los tsim cov hlwv complexes uas txhawb nqa IL-18 thiab gastrin D-induced apoptosis [109] .

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3.3. Txoj hnyuv Autoimmunity: Yuav ua li cas lub plab Neural Network koom nrog cov kab mob pathogenic

ENS tswj ntau yam kev ua haujlwm hauv plab hnyuv xws li lub plab motility, uas tuaj yeem cuam tshuam los ntawm kev kis kab mob neuropathy lossis neuronal cell tuag [22,23]. Enteric-associated neurons yog ze ze nrog lub cev tiv thaiv kab mob thiab tsis tu ncua saib xyuas thiab tswj lub plab homeostatic functions, nrog rau kev txav mus los thiab kev xav ntawm cov khoom noj [111]. Cov kab mob plab hnyuv tuaj yeem ua rau muaj kev hloov pauv tsis tu ncua hauv cov hnyuv nrog los ntawm kev txo qis ntawm cov myenteric neurons tshwm sim los ntawm NLRP6- thiab caspase-11- kho apoptosis. Hauv qhov sib piv, plab hnyuv myenteric macrophages tuaj yeem teb sai rau cov kab mob hauv plab kom txwv tsis pub kis kab mob uas ua rau enteric neuronal tuag los ntawm 2-adrenergic-arginase 1-polyamine axis signaling pathway [111]. Kev kis kab mob los ntawm cov kab mob sib txawv ntawm txoj hnyuv, nrog rau cov kab mob thiab kab mob, ua rau muaj kev tiv thaiv phenotype hauv plab hnyuv myenteric txheej macrophages, yog li ua lub luag haujlwm hauv kev tiv thaiv enteric neuronal hlwb thiab plab hnyuv physiological ua haujlwm thaum kis kab mob tom ntej [112]. Kev saib xyuas cov ntaub so ntswg homeostasis thiab kho kev raug mob hauv plab yuav tsum muaj kev sib koom ua ke ntawm ntau hom cell, nrog rau cov hlwb epithelial, lub cev tiv thaiv kab mob, stromal hlwb, thiab glial hlwb [23]. Glial thiab pericytes nyob rau hauv txoj hnyuv yog nyob rau hauv kev sib cuag nrog vascular endothelial hlwb thiab sib sau ua lub plab-vascular barrier (GVB) [113]. Spadoni et al. qhia tias GVB tswj kev nkag ntawm antigens thiab cov kab mob mus rau hauv cov hlab ntsha; plab hnyuv glial hlwb tuaj yeem kis tau thiab tau txais cov cim qhia los ntawm enteric neurons thiab IEC kom tswj tau GVB, uas muaj cov kab mob diffusible yim zaug loj dua li cov ntshav-hlwb teeb meem; murine typhoid Salmonella kab mob txhim kho -catenin signaling txoj hauv plab hnyuv epidermal hlwb tab sis inhibits txoj kev -catenin nyob rau hauv vascular endothelial hlwb, ua rau cov kab mob kis los ntawm GVB (Daim duab 2) [114]. ENS yog qhov loj tshaj plaws neural organ sab nraum lub hlwb thiab tuaj yeem ua haujlwm tau zoo hauv kev teb thiab hloov mus rau cov teeb meem hauv zos [115]. Lub innervation system nyob rau hauv cov ntaub so ntswg gastrointestinal yog ib qho tseem ceeb rau kev saib xyuas ntawm ib txwm gastrointestinal muaj nuj nqi [23]. Lub plab zom mov yog innervated los ntawm txawv teb chaws neurons los ntawm dorsal cag ganglion thiab vagal ganglion thiab tseem tswj los ntawm built-in neurons nyob rau hauv cov leeg nqaij thiab submucosa [22]. Ntawm lawv, cov kab mob hauv plab hnyuv (Nociceptor Neurons) yog cov receptors tseem ceeb hauv plab hnyuv thaum cov mob visceral mob thiab raws plab tshwm sim, ua rau mob thiab tiv thaiv mob neural reflexes [116,117]. Kev raug mob receptors muaj peev xwm cuam tshuam nrog plab hnyuv microbes thiab plab hnyuv hlwb thiab koom nrog hauv kev tswj hwm txoj hnyuv mucosal. Dorsal cag ganglion raug mob receptors tau pom los tiv thaiv colonization, ntxeem tau, thiab plab hnyuv kis ntawm STm. Kev raug mob receptor tswj tus naj npawb ntawm ileal Peyer's thaj (PP) follicle-associated epithelia (FAE) M hlwb thiab cov kab mob segmented filamentous (SFB) los ntawm kev tso tawm calcitonin gene-related peptide (CGRP), yog li txwv STm ntxeem tau [116]. SFB yog cov kab mob plab hnyuv uas ua rau cov kab mob ileal villi thiab PP FAE, thiab SFB induces histone modifications in IECs at retinoic acid receptor-rich motif sites to promote RA-associated defenses against pathogenic bacterial infections in the organism [118]. CGRP yog ib qho neuropeptide uas tswj cov neutrophil thiab dendritic cell teb nyob rau hauv lub cev [119], tswj M-cell thiab SFB qib hauv cov hnyuv los tiv thaiv tus kab mob Salmonella, thiab ua lub luag haujlwm tseem ceeb hauv ILC2 homeostasis thiab teb (Daim duab 2) [120 ]. Cov kev tshawb pom no qhia txog lub luag haujlwm tseem ceeb ntawm kev raug mob receptor neurons hauv kev nkag siab thiab tiv thaiv cov kab mob hauv plab.

Txoj hnyuv mucosal tiv thaiv kab mob ua lub luag haujlwm tseem ceeb hauv kev saib xyuas ntawm cov nroj tsuag commensal thiab tiv thaiv kab mob hauv plab hnyuv [23]. Yav dhau los, lub luag haujlwm no tau xav tias yuav tsum tau kho kom haum xeeb feem ntau los ntawm cov kab mob hauv plab hnyuv thiab plab hnyuv epithelium, tab sis cov kev tshawb fawb tsis ntev los no tau taw qhia tias ENS kuj tseem tuaj yeem ua lub luag haujlwm tseem ceeb [22]. IL-18 tau tshwm sim los ua ib qho tseem ceeb pleiotropic cytokine rau homeostasis thiab tus tswv tsev tiv thaiv hauv txoj hnyuv. Nyob rau hauv lub cev tiv thaiv kab mob, IL-18 yog ib tug pro-inflammatory cytokine uas yuav tsum tau los tawm tsam invasive kab mob xws li STm. Txawm li cas los xij, IL-18 ntawm epithelial thiab lub cev tiv thaiv kab mob hauv lub hauv paus chiv keeb tsis muaj kev tiv thaiv kab mob hauv plab hnyuv STm [121]. Cov hlab ntsha enteric ncaj qha tsim cov cytokine IL-18, uas nyob rau hauv lem tsub kom qhov kev qhia ntawm AMP nyob rau hauv cupped hlwb kom ntxiv dag zog rau txoj hnyuv tiv thaiv kab mob ntxeem tau [122]. Tsis zoo li lub cev tiv thaiv kab mob thiab cov chaw epithelial, cov neurons uas qhia IL-18 tsis yog redundantly qhia cov hlwb rau qhov kev tsim tawm AMP, txhawb kev tsis muaj menyuam hauv plab thaum lub sij hawm homeostasis, thiab pab tua cov kab mob hauv plab thaum kis kab mob (Daim duab 2). ENS yog ib ceg tseem ceeb ntawm kev tiv thaiv kab mob hauv lub cev, tsis yog rau kev sib koom ua ke ntawm mucosal barrier homeostasis tab sis kuj tiv thaiv kab mob kis kab mob [22].

3.4. Kev Tiv Thaiv Kev Noj Qab Haus Huv: Kev Tawm Tsam rau Micronutrients ntawm Tus Tswv Cuab-Pathogen Interface

Hlau ions yog ib qho ntawm cov khoom noj tseem ceeb hauv cov kab mob thiab cov tswv. Txhawm rau txwv cov kab mob, tus tswv tsev lub cev tiv thaiv kab mob hauv lub cev tau hloov kho ntau txoj hauv kev los txwv kev siv nws cov hlau ions los ntawm cov kab mob pathogenic, cov txheej txheem hu ua "kev tiv thaiv kev noj haus" [123]. Yog li ntawd, cov kab mob pathogenic kuj tau hloov kho cov txheej txheem los tiv thaiv kev tiv thaiv kev noj zaub mov zoo, feem ntau yog siv ntau lub tshuab thauj mus los thauj cov hlau ions mus rau hauv cov kab mob hlwb kom ua tiav cov kab mob loj hlob [124]. Lub peev xwm ntawm cov kab mob pathogenic sib tw nrog cov kab mob commensal rau cov as-ham yog qhov tseem ceeb rau lawv txoj sia nyob hauv plab [125]. Yav tas los, kev saib xyuas tau tsom mus rau yuav ua li cas hlau txwv txwv tsis pub cov kab mob loj hlob, tab sis muaj cov pov thawj loj hlob uas cov tswv kuj siv cov tshuaj lom ntawm cov hlau rau cov kab mob hauv lub cev ncaj qha [126]. Ntxiv nrog rau cov kab mob, ntau cov kab mob ua lub luag haujlwm tseem ceeb hauv kev kis kab mob. Piv txwv li, zinc inhibits viral protease thiab polymerase enzymatic cleavage txheej txheem, nrog rau cov kab mob txuas, kab mob, thiab decapitation, thaum ua lub luag haujlwm tswj hwm hauv T cell-mediated antiviral immunity [127]. Kev tiv thaiv kev noj haus yog ib qho txheej txheem tseem ceeb uas cuam tshuam thaum kis kab mob-cov kab mob sib kis. Respiratory syncytial virus (RSV) kab mob txhawb Pseudomonas aeruginosa (P. aeruginosa) biofilm kev loj hlob los ntawm dysregulation ntawm trophic tiv thaiv kab mob thiab ntxiv tso cai rau apical tso tawm ntawm transferrin, yog li ua kom cov hlau bioavailability rau P. aeruginosa biofilm loj hlob hauv vivo thiab hauv vitro [128]. Cov kab mob ua pa ua pa dysregulate tus tswv tsev hlau homeostasis thiab txhawb cov kab mob phem thib ob. Qhov no ntxiv rau peb txoj kev nkag siab txog cov txheej txheem ntawm kev sib kis kab mob-cov kab mob sib kis. Extracellular vesicles kuj koom rau hauv kev hloov pauv trophic hla ciam teb thaum muaj kab mob-viral co-kab mob [129]. Ua haujlwm ecological niches hauv kev kis kab mob los ntawm kev sib tw rau cov hlau ions yog ib qho kev hloov hauv kev sib koom ua ke, tab sis kev tshawb fawb txog kev noj zaub mov zoo ntawm cov kab mob hauv plab yog nyob rau hauv lawv cov me nyuam mos, Peb tseem tuaj yeem mine cov ntaub ntawv los ntawm lawv kom tau txais kev pom ntau ntxiv rau kev sib cuam tshuam ntawm cov kab mob sib txawv hauv kev sib kis. Hlau koom nrog DNA replication thiab cell proliferation, tua kab mob los ntawm khi lactoferrin thiab transferrin thiab interacting nrog neutrophils. Cov qib hlau ntau dhau tuaj yeem ua rau cov kab mob kis tau zoo thiab qhov hloov pauv ntawm cov kab mob [126]. Ntxiv nrog rau kev tswj hwm qib hlau hauv ib lub hlwb los tswj cov hlau tsim cytotoxicity, kev tswj ntawm cov hlau faib kuj yog ib qho kev tiv thaiv kab mob hauv lub cev uas tiv thaiv kev cuam tshuam ntawm cov kab mob mus rau hauv cov kab mob. Tus effector ntawm STm, SpvB encoded los ntawm pSLT, tswj cov hepcidin-ferroportin axis los ntawm IL-6/JAK/STAT3 txoj hauv kev, ua rau txo qis hauv cellular hlau thauj thauj ferritin thiab exacerbating dysregulation ntawm lub cev hlau metabolism (Daim duab 2 ). Nyob rau tib lub sijhawm, SpvB txhawb kev tsim cov tshuaj tiv thaiv kab mob uas cuam tshuam nrog cov kab mob ntawm tes infiltration los ntawm kev txhim kho TREM -1 txoj kev taw qhia [130,131]. Ib txoj hauv kev zoo sib xws muaj nyob rau hauv kab mob enterovirus. Coxsackievirus B3 (CVB3) kab mob ntawm Balb/c nas induces txawv upregulation ntawm gene qhia ntawm metallothionein (MT1), divalent hlau transporter 1 (DMT1), thiab hepcidin nyob rau hauv txoj hnyuv thiab daim siab, ua rau kom nce nyob rau hauv tooj liab / zinc (Cu /Zn) piv hauv cov ntshav [132]. Txo cov hlau dawb los ntawm kev ntxiv exogenous lipocalin 2, tus tswv tsev hlau chelating protein, txo cov kab mob hauv lub cev thaum kis kab mob-cov kab mob sib kis [129]. Ntawm qhov sib cuam tshuam ntawm tus tswv tsev thiab cov kab mob, calmodulin siv tshuaj tua kab mob los ntawm kev sib tw los yog chelating pathogenic zinc thiab manganese, inactivating pathogens thiab ua rau lawv tsis muaj zog tiv thaiv lub cev tiv thaiv kab mob teb [133]. Qee zaum, cov kab mob tau tsim muaj peev xwm los sib tw nrog calmodulin-mediated plab hnyuv hlau tshaib plab. STm kov yeej calprotectin-mediated zinc chelation los ntawm kev qhia txog kev sib koom siab zinc thauj cov protein ntau (ZnuACB), tso cai rau STm kom proliferate ib txwm nyob rau hauv lub ntsej muag ntawm plab hnyuv o thiab ua kom cov kab mob sib kis tau zoo [134]. Feem ntau cov kab mob, xws li E. coli, Salmonella, thiab Brucella, noj zinc thiab tiv thaiv zinc deficiency los ntawm ZnuACB uptake system [135]. Lub caij no, STm siv tib lub tswv yim los tawm tsam kev sib cais ntawm manganese los ntawm calmodulin. Lub peev xwm ntawm cov kab mob kom tau txais manganese, dhau los, txhawb kev ua haujlwm ntawm SodA thiab KatN, enzymes uas siv cov hlau ua cofactors los detoxify reactive oxygen hom. Qhov kev ua haujlwm ntawm manganese-dependent SodA no tso cai rau cov kab mob evade calprotectin thiab cov pa oxygen reactive hom-mediated neutrophil tua (Daim duab 2). Yog li, manganese tau txais tso cai rau STm kov yeej cov tshuaj tiv thaiv kab mob thiab txhawb nqa nws txoj kev loj hlob ntawm txoj hnyuv [133]. Ntxiv nrog rau kev tiv thaiv tsis zoo rau kev tiv thaiv kev noj zaub mov zoo, tus kab mob kuj tseem siv lub luag haujlwm tseem ceeb hauv kev txhawb kev kis kab mob los ntawm kev hloov kho ntawm qee yam ions. Hauv cov kab mob ntawm tes thiab tib neeg lub plab zoo li lub cev, RV kis tau ib feem ntawm IECs, thiab cov kab mob kis tau tso tawm adenosine 50 -diphosphate (ADP), uas ua rau P2Y1 purinergic receptors nyob rau hauv ib puag ncig cov hlwb ua rau muaj kev nce ntxiv hauv cov cellular calcium ion concentrations uas txhawb nqa. tus kab mob tus kheej replication. Nws tau pom tias RV tuaj yeem siv paracrine purinergic signaling txoj hauv kev ntawm cov hlwb los tsim cov kab mob calcium uas cuam tshuam rau lub cev, uas ua rau kom muaj kev cuam tshuam ntawm IECs thiab hloov cov kab mob plab hnyuv ntawm cov neeg mob, ua rau mob raws plab (Daim duab 2) [136].

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3.5. Lub plab Microbiota thiab Co-Infections: Ib qho kev sib cuam tshuam

Lub plab mammalian nyob hauv trillions ntawm cov kab mob, feem ntau yog cov kab mob uas tau koom nrog lawv cov tswv hauv kev sib raug zoo. Lub luag haujlwm tseem ceeb ntawm microbiota yog los tiv thaiv lub plab los ntawm cov kab mob exogenous thiab muaj feem cuam tshuam cov kab mob endogenous los ntawm ob peb lub tswv yim, suav nrog kev sib tw ncaj qha rau cov khoom noj tsis txaus thiab kev hloov pauv ntawm tus tswv lub cev tiv thaiv kab mob [137]. Cov txiaj ntsig tseem ceeb ntawm microbiota rau tus tswv tsev muaj xws li kev zom zaub mov carbohydrate thiab kev xa khoom, kev tsim cov vitamin, kev loj hlob ntawm cov kab mob qog nqaij hlav hauv plab, polarization ntawm lub plab tshwj xeeb tiv thaiv kab mob, thiab tiv thaiv kab mob colonization. Nyob rau hauv lem, lub plab tsis muaj zog teb induced los ntawm commensal flora tswj cov muaj pes tsawg leeg ntawm microbiota. Txawm li cas los xij, kev sib raug zoo ntawm tus tswv tsev thiab microbiota cuam tshuam thaum cov kab mob nkag mus. Cov qauv nrog rau kev nplua nuj ntawm plab hnyuv microbiome yog hloov pauv, uas tuaj yeem ua rau muaj kev cuam tshuam los yog cuam tshuam rau cov kab mob [137]. Kev nkag siab txog kev sib cuam tshuam ntawm cov kab mob-viral co-kis kab mob hauv plab microbiome tuaj yeem pab tsim cov tswv yim los tswj cov microbiome los tua cov kab mob sib kis [125]. Kab mob plab hnyuv co-kab mob cuam tshuam kev hloov pauv hauv microbial abundance txuam nrog ib leeg kab mob. Shilu Mathew et al. soj ntsuam cov kab mob plab hnyuv microbiota hauv cov menyuam yaus uas muaj ob tus kab mob loj, RV thiab NoV, thiab ob tus kab mob pathogenic, EAEC thiab EPEC, ib leeg lossis hauv kev sib koom ua ke. Cov txiaj ntsig tau pom tias kev nplua nuj ntawm tsev neeg Bifidobacterium li probiotics tau nce ntxiv nrog qhov hnyav ntawm cov kab mob sib xyaw ua ke ntawm cov kab mob. Cov txheeb ze ntawm Bifidobacteria tau txo qis hauv cov kab mob RV thiab NoV thiab ntau ntxiv hauv cov kab mob sib kis kab mob E. coli. Txawm hais tias sib xyaw EAEC cov kab mob ua rau muaj qhov sib txawv ntawm microbiota piv rau cov kab mob sib kis ib leeg lossis sib xyaw EPEC cov kab mob, kev sib koom ua ke ntawm cov kab mob E. coli exacerbated cov tsos mob hauv cov menyuam yaus [13].

Cov hnyuv microbiota cuam tshuam rau tus kab mob replication nyob rau hauv lub plab hnyuv thiab kab mob. Sharon K. Kuss et al. tshem tawm cov hnyuv ntawm cov nas nrog tshuaj tua kab mob thiab tom qab ntawd kis lawv nrog PV. Nws tau pom tias kev tuag ntau dua hauv cov nas uas tsis tau kho dua li cov nas uas tau siv tshuaj tua kab mob thiab qhov rov ua kom cov kab mob fecal rov qab mus rau hauv pab pawg nas uas kho tau tshuaj tua kab mob txhim kho PV kab mob. Cov txiaj ntsig no qhia tias cov nas uas muaj microbiota txhawb nqa PV replication zoo dua cov nas uas tsis muaj microbiota (Daim duab 2) [55]. PV khi rau cov kab mob microbial-sociated nto polysaccharides txhim khu kev tiv thaiv kab mob thaum tshav kub kub thiab txuas rau cov tswv tsev. Tus kab mob no yuav tau hloov zuj zus mus siv lub plab microbes ntawm qhov chaw tsim nyog tshaj plaws rau kev sib kis raws li qhov ua rau rov ua dua tshiab [52,56]. Hauv tib txoj hlab ntsha, cov tshuaj tua kab mob tiv thaiv kab mob MNoV tsis tu ncua, ib qho kev cuam tshuam uas tau thim rov qab los ntawm kev ntxiv cov kab mob microbiota. Cov tshuaj tua kab mob tsis tiv thaiv cov ntaub so ntswg los yog cuam tshuam rau cov kab mob sib kis, tab sis tshwj xeeb tshaj yog nyob rau hauv txoj hnyuv. Cov tshuaj tiv thaiv kab mob cytokines interferon λ receptor, Ifnlr1, thiab cov ntaub ntawv hloov pauv Stat1 thiab Irf3 yog xav tau rau cov tshuaj tua kab mob los tiv thaiv kab mob persistence. Yog li, cov kab mob microbiota txhawb nqa enterovirus persistence nyob rau hauv ib yam uas yog counteracted los ntawm tej yam ntawm lub cev tiv thaiv kab mob [49]. Cov pab pawg neeg enterovirus tseem muaj lub luag haujlwm tseem ceeb hauv kev saib xyuas cov hnyuv homeostasis. Ntxiv nrog rau cov kab mob tshwj xeeb tuaj yeem pab cov nas tiv thaiv kab mob txhim kho lawv lub peev xwm tiv thaiv kab mob enterovirus, thiab qhov kev tiv thaiv kab mob no tuaj yeem hloov mus ntawm cov tswv los ntawm kev sib kis ntawm cov kab mob sib kis. Cov txiaj ntsig tau qhia txog lub luag haujlwm ntawm enteroviruses hauv kev tiv thaiv kab mob hauv plab thiab pab tshawb xyuas cov txheej txheem ntawm enterovirus pawg-tus tswv kev sib cuam tshuam [41]. Nov yog tus kab mob no tiv thaiv txoj hnyuv los ntawm kev raug mob los ntawm eliciting ib qho IFN-I cov lus teb nyob rau hauv cov hnyuv nas, qhov twg IFN-I ua rau IECs kom nce qhov feem ntawm CCR2-dependent macrophages thiab IL- 22- tsim cov lymphocytes ntuj, yog li txhawb pSTAT3 signaling hauv IECs. MNV kab mob ua lub luag haujlwm tiv thaiv hauv DSS-induced plab hnyuv raug mob thiab plab hnyuv kab mob tshwm sim los ntawm Citrobacter rhamnosus (Daim duab 2) [42,138].

4. Cov lus xaus

Nws tau pom tias cov kab mob thiab cov kab mob sib kis tuaj yeem tshwm sim hauv ntau qhov chaw, suav nrog cov kab mob ua pa thiab txoj hnyuv. Lub plab hnyuv yog ib qho kev sib txuam thiab ib puag ncig, uas yog qhov nyuaj ntxiv los ntawm cov kab mob pathogenic stimuli thiab suav nrog ntau yam. Cov thev naus laus zis tshiab xws li kev sib koom ua ke siab (metagenomics, metabolomics, metallomics, thiab lwm yam) tso cai rau peb nkag siab cov kab mob hauv plab hnyuv los ntawm kev pom dav; organoid qauv simulate lub plab hnyuv ib puag ncig ntau dua li cov hlwb ib leeg hauv kev kuaj kab mob, thiab ib leeg-cell sequencing muab kev nkag siab zoo txog kev loj hlob ntawm intracellular los ntawm lub cellular foundations. Hauv kev xaus, txoj kev tshawb fawb ntawm txoj hnyuv kab mob sib koom ua ke tau nkag mus rau theem tshiab thiab nthuav dav dua, tab sis muaj ntau txoj haujlwm yuav tsum tau ua kom paub meej ntxiv cov txheej txheem ntawm kev sib cuam tshuam ntawm cov kab mob-viral-gut. Los ntawm kev tsom mus rau cov kab mob-cov kab mob thiab cov kab mob-tus tswv kev sib cuam tshuam, tsis yog ntawm cov kab mob xwb, nws muaj peev xwm siv cov txheej txheem no los txheeb xyuas cov hom phiaj kho tshiab.

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