Ceev Induction Ntawm Kev Tiv Thaiv Kev Tiv Thaiv Pneumonic Plague Los Ntawm Yersinia Pestis Polymeric F1 Thiab LcrV Antigens
May 26, 2023
Abstract:
Hauv kev tshawb fawb tsis ntev los no, peb tau pom tias kev txhaj tshuaj tiv thaiv nrog polymeric F1 capsule antigen ntawm tus kab mob plague pathogen Yersinia pestis ua rau muaj kev cuam tshuam sai ntawm kev tiv thaiv lub cev tiv thaiv kab mob los ntawm kev ua kom muaj zog ntawm innate-zoo li B1b hlwb. Conversely, lub monomeric version ntawm F1 ua tsis tau tejyam los tiv thaiv cov tsiaj tiv thaiv tam sim ntawd nyob rau hauv cov qauv ntawm tus kab mob plague. Hauv txoj kev tshawb no, peb tau tshuaj xyuas lub peev xwm ntawm F1 kom pom qhov pib sai ntawm kev tiv thaiv kev tiv thaiv kab mob hauv cov nas nyuaj ntawm tus kab mob plague. Kev txhaj tshuaj nrog ib koob ntawm F1 adsorbed ntawm aluminium hydroxide elicited zoo tiv thaiv tiv thaiv tom qab tuag intranasal raug rau ib tug tag nrho virulent Y. pestis hom nyob rau hauv ib lub lis piam. Qhov zoo siab, qhov sib ntxiv ntawm LcrV antigen txo lub sij hawm xav tau kom ua tiav cov kev tiv thaiv sai sai rau 4-5 hnub tom qab txhaj tshuaj. Raws li pom yav dhau los, cov qauv polymeric ntawm F1 yog qhov tseem ceeb hauv kev them nyiaj rau kev tiv thaiv kev tiv thaiv kev tiv thaiv los ntawm kev txhaj tshuaj tiv thaiv LcrV. Thaum kawg, hauv txoj kev tshawb fawb txog kev ua neej ntev, ib qho tshuaj tiv thaiv ib leeg nrog polymeric F1 ua rau muaj kev xav ntau dua thiab zoo ib yam li cov tshuaj tiv thaiv zoo sib xws nrog monomeric F1. Txawm li cas los xij, nyob rau hauv qhov teeb meem no, qhov tseem ceeb ntawm LcrV rau kev tiv thaiv ntev ntev tiv thaiv kev nyuaj siab ntsws tau rov hais dua.
Muaj kev sib raug zoo ntawm kev tiv thaiv humoral tiv thaiv kab mob thiab tiv thaiv kab mob. Kev tiv thaiv humoral tiv thaiv kab mob yog kev tiv thaiv cov lus teb ntawm lub cev tiv thaiv kab mob txawv teb chaws, uas yog koom nrog cov tshuaj tiv thaiv. Kev tiv thaiv kab mob yog hais txog lub cev muaj peev xwm tiv thaiv kev cuam tshuam ntawm cov kab mob txawv teb chaws. Cov tshuaj tiv thaiv humoral tiv thaiv kab mob tuaj yeem txhawb kev tua cov kab mob hauv lub cev, txhim kho lub cev tiv thaiv, thiab yog li txhim kho kev tiv thaiv. Tsis tas li ntawd, kev tiv thaiv kev tiv thaiv kab mob kuj tseem tuaj yeem tswj hwm qhov sib npaug ntawm lub cev tiv thaiv kab mob, tswj kev ua haujlwm ntawm lub cev tiv thaiv kab mob, thiab tsis txhob muaj kev cuam tshuam ntau dhau thiab tshwm sim ntawm cov kab mob autoimmune. Yog li, kev tiv thaiv kev tiv thaiv kab mob humoral yog qhov tseem ceeb los tswj lub cev kev noj qab haus huv thiab txhim kho kev tiv thaiv. Tsis tas li ntawd, kev tiv thaiv tib neeg kuj tseem ceeb heev, uas tuaj yeem tiv thaiv peb los ntawm kev tawm tsam los ntawm cov kab mob. Cistanche tuaj yeem txhim kho kev tiv thaiv. Cistanche yog nplua nuj nyob rau hauv ntau yam antioxidants, xws li vitamin C, vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals, Txo oxidative kev nyuaj siab thiab txhim kho lub cev tiv thaiv kab mob.
Nyem cistanche tubulosa cov txiaj ntsig
Ntsiab lus:
txhaj tshuaj tiv thaiv; pneumonic plague; kev tiv thaiv sai; Polymeric F1; monomeric F1; LcrV; nas qauv.
1. Taw qhia
Cov kab mob Gram-negative Yersinia pestis ua tus neeg sawv cev ntawm bubonic thiab pneumonic plague. Ntau pua lab tus neeg tau tuag vim qhov xwm txheej tuag ntawm kev kis kab mob los ntawm cov kab mob phem no hauv peb qhov kev sib kis loj thiab hauv ntau qhov kev sib kis hauv zos tau sau tseg hauv ob txhiab xyoo dhau los [1,2]. Vim tias nws muaj kab mob siab heev thiab ua rau tuag taus, Y. pestis raug cais raws li tus neeg sawv cev bioterror (https://www.cdc.gov/plague/ bioterrorism/index.html, nkag rau 9 Lub Xya Hli 2021). Txij li thaum tshawb pom thiab siv cov tshuaj tua kab mob dav dav, qhov tshwm sim thiab kev tuag los ntawm tus kab mob plague tau ploj zuj zus mus [3,4].
Txawm li cas los xij, kev kho tshuaj tua kab mob tiv thaiv tus kab mob plague muaj kev txwv; kom ua tau zoo, cov kev kho mob yuav tsum tau ua kom sai tom qab pib cov tsos mob uas, thaum pib, zoo ib yam li cov kab mob ua pa sab saud thiab yog li feem ntau misdiagnosed. Ib qho kev ncua sijhawm ntawm kev tswj hwm cov tshuaj tua kab mob tshwj xeeb rau kev kho mob plague tuaj yeem ua rau lawv cov txiaj ntsig tsis zoo thiab ua rau muaj kev tuag tseem ceeb ntawm cov neeg kho mob [5]. Kev cais tawm tsis ntev los no ntawm Y. pestis hom kab mob tiv taus ntau yam tshuaj tua kab mob, suav nrog cov kev pom zoo rau kev kho mob, thiab kev txhawj xeeb tias cov phenotypes hloov pauv tuaj yeem ua phem rau cov kab mob phem rau kev ua tsov rog lom neeg lossis bioterrorism xav tau kev txhim kho ntawm kev tiv thaiv ntxiv [6-8] . Tseeb tiag, tsis ntev los no daim ntawv thov ntawm cov tshuaj tua kab mob thib ob, kev kho mob ntxiv, thiab kev sib xyaw ntawm cov tshuaj tua kab mob thiab phage therapy qhia tau tias muaj txiaj ntsig zoo hauv tus qauv nas ntawm tus kab mob plague [9,10].
Peb tsis ntev los no tau pom tias siv tus qauv nas ntawm tus kab mob plague uas kev tswj hwm ntawm F1 capsular antigen ntawm Y. pestis elicits tiv thaiv kab mob nyob rau hauv ib hnub thiab, yog li ntawd, muaj peev xwm ua hauj lwm pab raws li kev kho mob rau kev tiv thaiv tus kab mob [11,12]. Qhov pib sai ntawm kev tiv thaiv no koom nrog kev ua kom sai ntawm innate-zoo li B1b hlwb uas nyob hauv peritoneal thiab pleural kab noj hniav, uas ua rau zus tau tej cov circulatory anti-F1 IgM thiab IgG antibodies [11,12]. Cov qauv polymeric ntawm F1 yog qhov tseem ceeb rau kev tiv thaiv kab mob plague sai, raws li tau pom los ntawm kev soj ntsuam tias, tsis zoo li polymeric F1, engineered monomeric ncig permutated F1 protein (monoF1) tsis koom nrog peritoneal B1b hlwb tam sim tom qab txhaj tshuaj, thiab Raws li, kev tsim cov tshuaj tiv thaiv F1 tau ncua sijhawm [12]. Hauv txoj kev tshawb no, siv tus qauv nas ntawm intranasal Y. pestis kab mob, peb tau tshuaj xyuas lub peev xwm ntawm F1 antigen los muab kev tiv thaiv sai tiv thaiv kab mob plague, uas sawv cev rau qhov tshwm sim loj tshaj plaws ntawm tus kab mob.
Txoj kev tshawb no tsim tau tias, xws li nyob rau hauv cov ntaub ntawv ntawm bubonic plague tiv thaiv kab mob, lub polymeric xwm ntawm F1 yog ib qho tseem ceeb rau sai thiab ntev tiv thaiv kab mob tom qab txhaj tshuaj tiv thaiv nrog ib koob tshuaj antigen. Txij li thaum F1 thiab LcrV antigens sawv cev rau feem ntau yuav cov neeg sib tw tshuaj tiv thaiv kab mob plague subunit thiab tau pom tias ua rau muaj kev tiv thaiv kab mob sai sai hauv tus qauv nas ntawm tus kab mob plague [13], peb tau txuas ntxiv txoj kev tshawb no los ntawm kev hais txog qhov muaj peev xwm txuas ntxiv txuas ntxiv kev tiv thaiv kev tiv thaiv. pneumonic plague los ntawm kev sib xyaw F1 nrog LcrV formulation.
2. Cov ntaub ntawv thiab cov txheej txheem
2.1. Nqe lus hais txog Ethics
Txoj kev tshawb no tau ua tiav nruj raws li cov lus pom zoo rau Kev Saib Xyuas thiab Kev Siv Cov Tsiaj Txhaum Cai ntawm National Institute of Health. Txhua qhov kev sim tsiaj tau ua los ntawm Israeli txoj cai lij choj thiab tau pom zoo los ntawm Pawg Saib Xyuas Kev Ncaj Ncees rau kev sim tsiaj hauv Israel lub koom haum rau Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Nyuaj Siab -IIBR M-64-19, IACUC-IIBR M-73-20). Tom qab qhov kev sib tw intranasal, cov nas raug saib xyuas txhua hnub. Tib neeg cov ntsiab lus kawg tau siv rau hauv peb cov kev tshawb fawb ciaj sia. Cov nas uas pom qhov poob ntawm txoj cai reflex tau euthanized los ntawm lub ncauj tsev menyuam dislocation.
2.2. Tsiaj
Rau-rau yim lub lis piam-laus inbred C67BL / 6 poj niam nas tau yuav los ntawm Envigo (Lub nroog Yeluxalees, Ixayees). Txiv neej thiab poj niam CD-1 cov hnub nyoog zoo sib xws tau yuav los ntawm Charles River (UK).
2.3. Tsiaj Txhaj Tshuaj Nrog Purified Antigens
PolyF1: Lub polymeric F1 protein yog purified los ntawm kab lis kev cai supernatant ntawm E. coli hlwb qhia lub caf1 operon ntawm Y. pestis Kimberley53 hom, raws li yav tas los tau piav nyob rau hauv [14]. Qhov hnyav molecular ntawm purified F1 tau txiav txim siab siab dua 1000 kDa los ntawm qhov loj-tsis suav chromatography siv Superdex 200 kem (Cytiva, MA, USA).
MonoF1: Lub plasmid pAH34L coding rau monomeric F1 (cpCaf1) tau ua siab zoo tau los ntawm Dr. Daniel Peters thiab Prof. Jeremy H. Lakey, Newcastle University, UK [15]. pAH34L tau nkag rau hauv Lemo21 (DE3) E. coli yuav los ntawm New England Biolabs (Ipswich, MA, USA). Randomly xaiv transformants tau zus ntawm 37 ◦C thiab 220 rpm nyob rau hauv Terrific broth ntxiv nrog ampicillin (200 µg / mL). Kev nthuav qhia tau tshwm sim hauv nruab nrab-caug los ntawm kev sib ntxiv ntawm isopropyl -thiogalactopyranoside (IPTG; 1 mM), thiab cov kab lis kev cai tau tom qab incubated ntawm 18 ◦C thiab 220 rpm rau ntxiv 19 h. Cov kab mob pellets raug hnyav (ntub hnyav) thiab solubilized nrog CelLytic ™ B cell lysis reagent raws li cov chaw tsim khoom cov lus qhia (Merck-Sigma, Rehovot, Israel).
Cov recombinant Tol3-cpCaf1 fusion protein tau ua kom huv los ntawm kev yooj yim ua kua chromatography (PFLC) ntawm HisTrap™ HP kem raws li cov chaw tsim khoom cov lus qhia (Cytiva, MA, USA). Lub Tol3 moiety tau sib cais los ntawm cpCaf1 los ntawm cleavage nrog thrombin (Merck-Sigma, Rehovot, Ixayees) thiab reabsorption ntawm lub qub ntawm ib tug regenerated HisTrap™ HP kem. Lub cpCaf1 (monoF1) moiety tau sau los ntawm qhov ntws-los ntawm feem thiab feem ntau dialyzed tawm tsam 1 × PBS. Endotoxins raug tshem tawm los ntawm Triton X-114 theem kev sib cais, raws li tau piav qhia yav dhau los hauv [16]. Protein kom muaj nuj nqis raug ntsuas siv txoj kev bicinchoninic acid (Pierce™ BCA Protein Assay Kit, Thermo). Lub purity ntawm monomeric F1 tau txheeb xyuas los ntawm SDS-PAGE ua raws li Coomassie xiav staining thiab los ntawm Western blot tsom siv luav anti-F1 cov tshuaj tiv thaiv, raws li yav dhau los tau piav qhia hauv [11].
LcrV: Qhov ntev-ntev LcrV coding sequence los ntawm virulent Y. pestis Kimberley53 strain tau cloned rau hauv pGEX qhia vector (GE Healthcare, Chicago, IL, USA) thiab nkag mus rau hauv E. coli hlwb. LcrV coding sequence tau pom zoo ib yam li LcrV ntawm Y. pestis CO92 hom. Recombinant LcrV tau tsim thiab ua kom huv raws li tau piav qhia los ntawm Leary li al. [17]. Endotoxins raug tshem tawm los ntawm LcrV purified raws li tau piav saum toj no.
Tag nrho ntawm 20 mus rau 160 µg ntawm polyF1 thiab LcrV los yog 80 µg ntawm monoF1 tau adsorbed ntawm 2 feem pua ntawm aluminium-hydroxide (AlOH) gel (Brennentag Biosector, Denmark) mus rau qhov kawg concentration ntawm 0.36 feem pua. Cov nas ib leeg tau txhaj tshuaj subcutaneously siv qhov ntim tas li ntawm 200 µL coj mus rau sab nraub qaum.
2.4. Tus cwj pwm ntawm Serological teb
Cov nas tau raug tus Tsov tus tw, thiab tus neeg IgG titers tsim tawm tsam F1 thiab LcrV hauv cov ntshav tau txiav txim los ntawm ELISA, raws li tau tshaj tawm yav dhau los hauv [11]. IgG1 thiab IgG3 titers tau ntsuas siv isotype-specific alkaline phosphatase-conjugated tshis anti-nas antibodies (Jackson Laboratories, Farmington, CT, USA).
Bronchoalveolar lavage (BAL): Cov nas tau muab tshuaj loog los ntawm cov tshuaj ketamine/xylazine, thiab cov hlab ntsha raug nthuav tawm, kev saib xyuas ntxiv kom tsis txhob los ntshav. Ib qho kev phais me me tau ua, thiab ib qho {{0}}} ntsuas qhov hloov tau yooj yim cannula (BD Neoflon™) tau ntxig thiab ruaj ntseg los ntawm kev phais phais. Lub ntsws raug ntxuav nrog 1 × PBS siv 1 mL luer-lock syringe uas tau txuas nrog lub cannula ruaj ntseg. Cov kua dej lavage uas kis tau los ntawm cov ntshav tau muab pov tseg. Cov kua dej lavage tau raug tshem tawm los ntawm centrifugation (400 × g, 4 ◦C), thiab cov supernatant tau ua kom tsis muaj menyuam lim ua ntej ELISA. Anti-F1 thiab anti-LcrV antibody concentrations hauv BAL kua (BALF) ntawm cov tsiaj txhaj tshuaj tau txiav txim siab siv diluted Mab 57 (F1) thiab Mab 59 (LcrV) yav dhau los qhia hauv [18] raws li cov qauv nkhaus suav nrog hauv txhua {{14} }zoo kuaj phaj. Cov kev txwv ntawm kev kuaj pom (LODs) rau cov tshuaj tiv thaiv-F1 IgG thiab cov tshuaj tiv thaiv-LcrV hauv BALF tau txiav txim siab tias yog 0.8 ng / mL thiab 0.15 ng / mL, feem.
2.5. Nas kab mob
Intranasal (hauv) kab mob tau ua raws li tau piav qhia yav dhau los hauv [19]. Luv luv, ib lub voj voog uas muaj cov kab mob Y. pestis Kim53 cov kab mob kab mob tau sau thiab diluted hauv plawv infusion broth (HIB, Difco) ntxiv nrog 0.2 feem pua xylose thiab 2.5 mM CaCl2 (Sigma-Aldrich, St. Louis, MO, USA) rau OD660 ntawm 0.01 thiab loj hlob rau 22 teev ntawm 28 ◦C thiab 100 rpm. Thaum kawg ntawm lub sij hawm incubation (OD660 ≈ 4), kab lis kev cai raug ntxuav thiab diluted nyob rau hauv saline (0.9 feem pua NaCl) mus rau qhov xav tau koob tshuaj uas tau raug txheeb xyuas los ntawm suav cov colony-forming units tom qab plating thiab incubating ntawm BHIA daim hlau (48 h. ntawm 28 ◦C). Cov nas raug tshuaj loog nrog kev sib xyaw ntawm 0.5 feem pua ketamine HCl thiab 0.1 feem pua xylazine thiab tom qab ntawd kis tus kab mob intranasally nrog 35 µL / nas ntawm cov kab mob ncua. Intranasal LD50 ntawm Kim53 hom rau C57BL/6 nas yog 1100 cfu thiab 2100 cfu rau CD-1 nas. Tus nqi LD50 tau suav nrog raws li txoj kev piav qhia los ntawm Reed thiab Muench [20]. Nas morbidity thiab tuag tau raug saib xyuas txhua hnub rau 21 hnub. Thaum kawg ntawm lub sijhawm no, kev tshem tawm cov kab mob tau txheeb xyuas los ntawm plating spleen homogenates los ntawm cov tsiaj muaj sia nyob mus rau BHIA daim hlau ntxiv nrog 200 µg / mL streptomycin (48 h ntawm 28 ◦C).
2.6. Tus cwj pwm ntawm tus nas qauv ntawm Pneumonic Plague
Cov nas uas muaj kab mob Intranasally raug tshuaj loog ntawm lub sijhawm taw qhia tom qab kis los ntawm kev daws teeb meem ntawm ketamine / xylazine, thiab cov ntshav heparinized tau kos los ntawm lub plawv dhia. Tom qab ntawd, mediastinal lymph node (mdLN), ntsws, thiab poov xab raug tshem tawm thiab mashed rau ib leeg-cell ncua mus rau 70 µm nylon mesh (cell strainer, Falcon, Corning, NY, USA) hauv 1 × PBS . Tus naj npawb ntawm Y. pestis Kim53 nyob rau hauv ntau yam kabmob thiab cov ntshav tau txiav txim los ntawm plating serially diluted cell suspensions mus rau BHIA daim hlau ntxiv nrog 200 µg / mL streptomycin. Rau kev soj ntsuam histological, nas tau tshuaj loog, thiab lawv cov tracheas tau cannulated raws li qhia saum toj no. Ib kem (0.7 × 30 cm, KONTES, St. Louis, MO, USA) tau ntim nrog cov tshuaj buffered formaldehyde (10 feem pua qhov kawg conc.) tau txuas nrog lub cannula, thiab lub ntsws tau "inflated" nkaus xwb los ntawm lub ntiajteb txawj nqus. Fixative-filled ntsws tau khaws cia rau hauv tib qhov tsis pub dhau 14 hnub thiab tom qab ntawd ua tiav los ua cov blocks paraffin-embedded. Ib-rau peb-micrometer seem tau stained nrog tus qauv eosin / hematoxylin (H&E) stain thiab nrog Masson-Goldner staining kit (Merck, Rehovot, Israel) rau kev kuaj pom ntawm fibrosis. Tsis tas li ntawd, cov hlab ntsws tau stained rau Y. pestis siv hauv tsev luav anti-F1 IgG cov tshuaj tiv thaiv (1:10,{20}}) thiab cov khoom siv Histostain®-SP (ZYMED®, Invitrogen, Waltham, MA, USA. ). Stained seem tau duab siv lub koob yees duab ICC3 txuas rau Axioscope A1 microscope (Zeiss, Lub teb chaws Yelemees).
2.7. Kev txheeb cais
Qhov tseem ceeb ntawm cov titers sau rau hauv nas uas muaj ntau tshaj ob pawg tau txiav txim siab los ntawm nonparametric Kruskal-Wallis nrog Dunn's post hoc test. Kev ntsuas ntsuas qib (Mantel-Cox) tau siv rau kev sib piv ntawm txoj kev ciaj sia tau txais hauv ntau pawg tshuaj tiv thaiv. Qhov sib txawv tau suav tias yog qhov tseem ceeb yog p Tsawg dua lossis sib npaug rau 0.05. Kev suav tau ua tiav siv GraphPad Prism software.
3. Cov txiaj ntsig
Hauv kev tshawb fawb yav dhau los, peb tau ua pov thawj tias kev txhaj tshuaj tiv thaiv nas nrog cov ntaub ntawv keeb kwm polymeric ntawm F1 capsular antigen ntawm Yersinia pestis ua rau muaj kev cuam tshuam sai ntawm kev tiv thaiv kab mob plague. Raws li, nws tau hais tias kev tswj hwm F1 yuav raug suav hais tias tsis yog tsuas yog kev tiv thaiv kev tiv thaiv nkaus xwb tab sis kuj yog kev pabcuam khomob thaum muaj xwm txheej ceev xws li kev sib kis uas tshwm sim los yog ua phem rau cov tshuaj tua kab mob tiv thaiv kab mob [12]. Nyob rau hauv tsab ntawv ceeb toom no, qhov kev tshem tawm ntawm kev tiv thaiv sai tau raug nug nyob rau hauv cov ntaub ntawv ntawm pneumonic plague siv cov qauv murine zoo uas muaj xws li raug nas mus rau cov kab mob los ntawm inoculation intranasal. Cov qauv no tau pom los khaws cov kab mob pathogenicity uas ua rau ua pa tshwm sim ntawm thawj tus kab mob plague (Ntxiv daim duab S1) [10,19,21–24].
3.1. Kev tiv thaiv sai sai tau txais los ntawm F1 thiab LcrV hauv Nas Model ntawm Pneumonic Plague
Lub peev xwm ntawm F1 antigen txhawm rau tiv thaiv kev tiv thaiv sai tau sim los ntawm kev sim uas C57BL / 6 nas tau txhaj tshuaj los ntawm ib qho kev tswj hwm ntawm AlOH-adsorbed polyF1 (20, 80, thiab 160 µg / nas), thaum cov tsiaj tswj tau txhaj tsuas yog nrog lub adjuvant. Lub peev xwm ntawm cov tshuaj tiv thaiv nas kom muaj sia nyob tus kab mob tuag intranasal nrog tus kab mob Y. pestis strain Kim53 (10LD50=11,{11}} cfu) tau soj ntsuam peb thiab xya hnub tom qab txhaj tshuaj tiv thaiv kev sib piv rau kev tswj tsiaj (Daim duab 1 ). Tom qab peb hnub, tsuas yog kev ncua sij hawm rau kev tuag thiab kev ciaj sia (ntawm qhov tsis txaus ntseeg qhov tseem ceeb) tau pom (Daim duab 1A). Kev ncua sijhawm ntawm kev txhaj tshuaj tiv thaiv thiab kev sib tw tsuas yog 4 hnub ntxiv (7 hnub nyob rau hauv tag nrho) tau pab cawm tag nrho cov nas uas tau txhaj tshuaj nrog cov koob tshuaj ntau ntawm polyF1 (80 thiab 160 µg / nas) nrog rau 87 feem pua ntawm cov nas uas tau txhaj tshuaj tiv thaiv kab mob. koob tshuaj tsawg ntawm polyF1 (Daim duab 1B).
Lub peev xwm ntawm F1 antigen los ua kom muaj kev tiv thaiv kab mob sai sai tiv thaiv tus kab mob pneumonic plague txhawb peb los tshuaj xyuas seb puas muaj kev txhaj tshuaj tiv thaiv kab mob ntxiv, LcrV, yuav txhim kho lub cev tiv thaiv kab mob ntawm cov tsiaj los ntawm kev nthuav tawm qhov pib ntawm kev tiv thaiv kab mob. Tseeb tiag, thaum qhov kev sib tw tua kab mob tua kab mob tau ua tiav 3 hnub tom qab txhaj tshuaj tiv thaiv ua ke, kev tswj hwm ntawm LcrV thiab polyF1 sib xyaw formulation (80 µg lossis 160 µg ntawm txhua tus antigens) tuaj yeem cawm 30-50 feem pua ntawm cov nas (Daim duab 1C). Qhov tshwj xeeb tshaj yog, txuas ntxiv lub sijhawm ntawm kev txhaj tshuaj tiv thaiv thiab kev sib tw mus rau xya hnub tau them nyiaj tiv thaiv tag nrho rau txhua tus tsiaj uas tau txhaj tshuaj ntawm txhua koob tshuaj antigens (Daim duab 1D). Lub peev xwm ntawm polyF1 ib leeg lossis ua ke nrog LcrV los tiv thaiv kev tiv thaiv kab mob ntsws sai sai hauv ib lub lis piam tsis cuam tshuam los ntawm kev nce qhov kev sib tw ntawm cov tshuaj intranasal los ntawm kaum npaug (Daim duab 1E), lees paub qhov muaj zog ntawm lub xeev tiv thaiv.
3.2. Kinetics ntawm Humoral teb tom qab txhaj tshuaj tiv thaiv nrog F1 thiab LcrV
Qhov kev soj ntsuam uas cov tshuaj tiv thaiv LcrV thiab F1 ua ke ua rau muaj kev tiv thaiv kev tiv thaiv sai sai tau qhia tias cov lus teb tsis txaus ntseeg tau raug tshem tawm sai tom qab ntawd. Txhawm rau hais txog qhov muaj peev xwm no thiab txiav txim siab qhov kev koom tes ntawm cov lus teb humoral tawm tsam txhua tus antigens los tiv thaiv Y. pestis, kinetics ntawm cov tshuaj tiv thaiv IgG tshwj xeeb tsim tawm tsam ob tus neeg antigens tau txheeb xyuas 5-9 hnub tom qab txhaj tshuaj tiv thaiv ib zaug. ntawm C57BL/6 nas nrog kev sib xyaw ntawm polyF1 thiab LcrV (Daim duab 2A). Raws li kev cia siab, raws li kev soj ntsuam yav dhau los, anti-F1 IgG antibody titers (GMT=1.35 × 103 ) twb kuaj tau nyob rau hauv sera ntawm tag nrho cov tsiaj txhaj tshuaj nyob rau hnub 5 postvaccination (Daim duab 2B).
Kev nce zuj zus ntawm cov tshuaj tiv thaiv-F1 IgG antibody titers tau pom nyob rau hauv cov hnub tom qab, mus txog ~60-fold ntau dua nyob rau hnub 9 tom qab txhaj tshuaj tiv thaiv (GMT=8.26 × 104, Daim duab 2B). Anti-F1 IgG cov tshuaj tiv thaiv kuj tseem tuaj yeem kuaj pom hauv cov kua hauv lub ntsws pib txij hnub 7 tom qab txhaj tshuaj tiv thaiv kab mob, nce siab txog li ~ 1 µg / mL rau hnub 9 (Daim duab 2C). Interestingly, thaum lub anti-LcrV humoral teb lagged piv rau qhov elicited los ntawm polyF1 (Hnub 7 GMT=613, daim duab 2D), ib tug ntau dua nyob rau hauv lub anti-LcrV IgG antibody qib tau ntsuas nyob rau hauv cov hnub tom qab, nthuav qhia ib tag nrho nce ntawm ~160-fold (GMT=1 × 105, Daim duab 2D). Anti-LcrV IgG cov tshuaj tiv thaiv kuj tseem tuaj yeem kuaj pom hauv cov kua hauv lub ntsws ntawm cov tshuaj tiv thaiv nas pib txij hnub 8, txawm hais tias qhov qis dua piv rau cov tshuaj tiv thaiv F1 (Daim duab 2E).
Qhov nce ntxiv hauv cov tshuaj tiv thaiv LcrV IgG titers, tau pom nyob rau Hnub 8-9 tom qab txhaj tshuaj tiv thaiv, tsis zoo li cuam tshuam nrog kev ua kom lub cev zoo li B1b hlwb, raws li tau hais los ntawm kev soj ntsuam tias IgG3 feem ntawm cov tshuaj tiv thaiv no tau kuaj pom hauv qab no piv rau cov anti-F1 IgG3 antibody feem ([12] thiab Supplementary Figure S2). Yog li, cov ntaub ntawv qhia tau hais tias LcrV tuaj yeem tsim cov lus teb sai sai, nrog rau F1, kev tiv thaiv zoo tiv thaiv kab mob plague thaum ntxov li ib lub lis piam tom qab txhaj tshuaj. Tsis tas li ntawd, kev soj ntsuam uas cov tshuaj tiv thaiv-F1 thiab anti-LcrV IgG cov tshuaj tiv thaiv tau sau rau hauv lub ntsws ntawm cov tsiaj txhaj tshuaj qhia tias cov lus teb hauv zos hauv lub ntsws yuav yog ib qho tseem ceeb rau kev ua tiav kev tiv thaiv kab mob ntsws.
3.3. Qhov tseem ceeb ntawm F1 Polymeric Structure rau qhov pib sai ntawm kev tiv thaiv kev tiv thaiv
Peb tau tshaj tawm cov kev tshawb pom yav dhau los txhawb nqa qhov kev xav tias quaternary polymeric architecture ntawm F1 yog qhov tseem ceeb rau nws lub peev xwm los txhawb kev tiv thaiv sai tiv thaiv kab mob plague [12]. Yog li ntawd, nyob rau hauv txoj kev tshawb no, qhov teeb meem no kuj tau hais nyob rau hauv cov ntaub ntawv ntawm kev tiv thaiv pneumonic plague. Cov nas tau txhaj tshuaj nrog monomeric lossis polymeric F1, nyob rau hauv ob qho tib si entailing coadministration LcrV (80 µg ntawm txhua antigen / nas). Peb, plaub, thiab tsib hnub tom qab ntawd, cov nas tau sib tw hauv cov tshuaj tua kab mob Y. pestis Kim53. Cov ntaub ntawv muaj sia nyob tau piav qhia hauv daim duab 3 qhia tias kev txhaj tshuaj nrog cov sib xyaw ntawm polyF1 thiab LcrV tiv thaiv 25 feem pua, 62.5 feem pua, thiab 87.5 feem pua ntawm cov nas, raws li (Daim duab 3A), los ntawm kev sib tw tuag.
Hauv qhov sib piv, txhua tus nas txhaj tshuaj tiv thaiv monoF1 thiab LcrV sib xyaw ua rau muaj tus kab mob tshwj tsis yog cov pab pawg tau txhaj tshuaj tiv thaiv 5 hnub ua ntej qhov kev sib tw, uas tau pom tias muaj kev tiv thaiv qis dua 25 feem pua (Daim duab 3B). Kev txhaj tshuaj nrog cov tshuaj tsis sib xyaw uas muaj xws li polyF1, monoF1, lossis LcrV (80 µg/nas) 4 hnub ua ntej qhov kev sib tw tsis tiv thaiv tsiaj. Txawm li cas los xij, kev txhaj tshuaj nrog polyF1 tau them nyiaj qeeb qeeb hauv kev tuag piv rau tag nrho lwm pawg sim (p <0.001; Daim duab 3C). Ua ke, cov txiaj ntsig no qhia meej meej tias daim ntawv polymeric ntawm F1 yog qhov tseem ceeb rau kev tau txais cov lus teb ceev ceev hauv kev sib xyaw nrog LcrV.
3.4. Tus cwj pwm ntawm Kev Tiv Thaiv Kev Tiv Thaiv Lub Sij Hawm Ntev Induced los ntawm Kev Tiv Thaiv Ib Leeg Nrog F1 thiab LcrV
Thaum kawg, peb tau tshuaj xyuas seb qhov kev tiv thaiv ntev ntev ntawm kev tiv thaiv kab mob pneumonic plague txawv ntawm cov nas uas tau txhaj tshuaj los ntawm monoF1 lossis polyF1. Raws li, CD1 nas tau txhaj tshuaj ib zaug nrog monoF1 lossis polyF1 ib leeg, nrog rau kev tswj hwm cov qauv uas suav nrog kev sib xyaw nrog LcrV. Qib ntawm cov tshuaj tiv thaiv tshwj xeeb hauv cov ntshav ntawm cov tsiaj txhaj tshuaj tau ntsuas rau lub hlis tom qab. Cov ntaub ntawv piav qhia hauv daim duab 4A qhia tias cov tshuaj tiv thaiv F1 IgG titers siab dua hauv txhua pab pawg tau txhaj tshuaj nrog polyF1 dua li cov tshuaj tiv thaiv monoF1. Siab thiab zoo ib yam los tiv thaiv LcrV IgG titers tau ntsuas hauv txhua tus nas uas tau txhaj tshuaj LcrV.
Ib lub sij hawm ntawm 6 lub hlis tom qab txhaj tshuaj (3 hnub tom qab rho ntshav rau kev txiav txim siab titer), cov nas tau sib tw hauv cov tshuaj tua kab mob uas muaj 100LD50 ntawm Y. pestis Kim53, thiab kev ciaj sia tau soj ntsuam rau 21 hnub (Daim duab 5). Cov nas uas tau txhaj tshuaj nrog polyF1 raws li ib qho tshuaj tiv thaiv nkaus xwb tsuas yog tiv thaiv qee qhov, thaum txhua tus nas uas tau txhaj tshuaj nrog monoF1 succumbed rau tus kab mob, zoo ib yam li tswj cov nas tsis zoo (Daim duab 5A). Qhov tshwj xeeb tshaj yog, cov tshuaj tiv thaiv F1 IgG titers uas tau ntsuas hauv sera ntawm polyF1- cov tsiaj txhaj tshuaj tsis pom muaj kev sib raug zoo nrog kev ciaj sia tiv thaiv kev nyuaj siab ntsws (Daim duab 5B). Qhov sib ntxiv ntawm LcrV tau ua kom muaj kev tiv thaiv tag nrho rau cov nas uas tau txhaj tshuaj nrog monoF1 thiab rau cov uas tau txhaj tshuaj nrog polyF1 (Daim duab 5A), qhia tias cov lus teb antiLcrV tau ua kom pom tag nrho ntawm kev tiv thaiv tus nqi ntawm cov lus teb los tiv thaiv F1. Cov txiaj ntsig zoo sib xws hais txog cov lus teb lom zem thiab muaj sia nyob raws li kev sib tw pulmonary tau txais nyob rau hauv cov tshuaj tiv thaiv txiv neej CD-1 nas (Ntxiv daim duab S3), qhia tias txoj kev tshawb no tsis cuam tshuam los ntawm kev sib deev tsiaj (nco ntsoov tias kev sim thawj zaug tau ua nrog poj niam tsiaj) .
Ua ke, cov txiaj ntsig no qhia tau tias F1 los ntawm nws tus kheej tuaj yeem ua rau qhov pib sai ntawm kev tiv thaiv kab mob plague, uas nyob ntawm nws cov qauv polymeric. Qhov sib ntxiv ntawm LcrV rau polyF1 tsis yog tsuas yog luv luv lub sij hawm yuav tsum tau ua kom tiav xws li kev tiv thaiv sai, tab sis kuj muab kev tiv thaiv ntev thiab muaj txiaj ntsig zoo tiv thaiv kev mob ntsws ntawm tus kab mob plague, raws li tau piav qhia yav dhau los.
4. Kev sib tham
Kev cais tawm tsis ntev los no ntawm Y. pestis hom kab mob uas tiv taus ntau yam tshuaj tua kab mob nrog rau cov kev pom zoo rau kev kho mob [8,25,26], yog los ntawm kev tshawb nrhiav ntxiv tiv thaiv kab mob plague, xws li cov tshuaj tiv thaiv uas ua rau muaj kev tiv thaiv sai, siab. pej xeem kev noj qab haus huv, thiab kev kho mob ntsig txog. Cov tshuaj tiv thaiv, feem ntau, yog suav tias yog kev tiv thaiv tiv thaiv kab mob sib kis thiab yog li xa mus rau cov neeg noj qab haus huv ntau xyoo ua ntej. Raws li, feem ntau ntawm cov kev tshawb fawb preclinical soj ntsuam kev txhim kho cov tshuaj tiv thaiv kab mob plague koom nrog kev txhaj tshuaj ntev ntev ua ntej muaj kev sib tw tuag [13,27–29]. Peb tau tshaj tawm yav dhau los tias kev txhaj tshuaj tiv thaiv nrog lub ntuj polymeric daim ntawv ntawm capsular F1 antigen ua rau muaj zog heev thiab muaj zog B-cell-dependent tiv thaiv kab mob uas tiv thaiv cov tsiaj txawm ob peb teev tom qab tuag subcutaneous Y. pestis kev sib tw [11,12].
Hauv cov kev tshawb fawb no, peb tau pom tias kev txhaj tshuaj ib zaug nrog F1 ua rau muaj cov tshuaj tiv thaiv F1 (IgM thiab IgG) hauv cov ntshav hauv ob peb hnub dhau los ntawm kev ua kom lub hlwb zoo li B1b. Cov subpopulation ntawm B hlwb no nyob hauv cov kab noj hniav ntawm cov nas thiab feem ntau tsim cov lus teb serological tawm tsam nonproteinaceous polymeric antigens, xws li LPS thiab polysaccharides uas tsim cov tshuaj ntsiav ntawm ntau cov kab mob (pneumococci, meningococci, thiab lwm yam) [30]. Cov tshuaj tiv thaiv kab mob sai no yog tus cwj pwm los ntawm T cell ywj pheej thiab tiam ntawm IgG3 murine antibody serotype. Peb tau pom tias tag nrho cov lus hais saum toj no kuj tseem siv tau rau cov lus teb tiv thaiv sai uas tsim los ntawm F1. Tsis tas li ntawd, peb tau pom tias cov xwm txheej polymeric ntawm F1 yog qhov tseem ceeb rau qhov kev tiv thaiv kab mob sai no, raws li monomeric F1 (tsim los ntawm kev hloov pauv ntawm cov noob caf1) ua tsis tau rau B1b hlwb, lagged tom qab cov polymeric F1 hauv IgG titer kinetics, tau ua. tsis tsim cov IgG3 serotype, thiab ua tsis tiav los muab kev tiv thaiv sai. Cov lus teb ceev no yog nrog los ntawm cov pa qeeb qeeb T-cell-dependent adaptive teb tawm tsam F1. Yog li ntawd, peb xav tias polymeric F1 ua rau ob lub serological teb ua nyob rau hauv parallel: ib tug uas yog T-cell- ywj siab ntawm B1b hlwb thiab qhov thib ob ib tug nrog follicular B hlwb nyob rau hauv ib tug T-cell-dependent yam [12].
Hauv tsab ntawv ceeb toom no, txoj kev tshawb fawb yav dhau los tau txuas ntxiv los ntawm kev hais txog lub peev xwm ntawm F1 antigen kom muaj kev tiv thaiv sai sai hauv cov qauv nas nyuaj ntawm tus kab mob ntsws. Peb qhia tau hais tias ib qho kev tswj hwm ntawm AlOH-adsorbed polymeric F1, xya hnub ua ntej muaj kev sib tw ua rau tuag taus nrog cov kab mob Y. pestis, tuaj yeem ua rau muaj kev tiv thaiv zoo (Daim duab 1). Qhov kev soj ntsuam xav tsis thoob no yuav luag tsis muaj qhov ua ntej, tsis yog hais txog qhov ceev ntawm cov tshuaj tiv thaiv nkaus xwb tab sis kuj hais txog qhov tseeb tias lub peev xwm ntawm F1 antigen kom muaj kev tiv thaiv hauv tus nas qauv ntawm tus kab mob plague tsuas yog tsis tshua hais txog [31]. Qhov kev soj ntsuam tau tshaj tawm ntawm no yog ua raws li cov ntaub ntawv sau tseg los ntawm Derbise thiab nws cov npoj yaig [32] txog kev kuaj pom cov tshuaj tiv thaiv F1 tsis ntev tom qab txhaj tshuaj tiv thaiv. Ntawm no, peb qhia tau hais tias qhov sib ntxiv ntawm LcrV rau polyF1 tsis yog tsuas yog muaj txiaj ntsig zoo nyob rau lub sijhawm ntev, raws li tau tshaj tawm yav dhau los [33,34], tab sis kuj tseem ua kom lub zog tiv thaiv kab mob tiv thaiv Y. pestis intranasal kev sib tw rau ob peb hnub xwb (Daim duab 2 thiab 5).
Lub peev xwm los tsim kev tiv thaiv sai tiv thaiv kab mob plague los ntawm kev txhaj tshuaj tiv thaiv nrog F1 thiab LcrV ntxiv dag zog rau cov kev tshawb pom zoo sib xws uas tau tshaj tawm yav dhau los los ntawm Williamson thiab cov npoj yaig [13], nyob rau hauv qhov kev txhaj tshuaj nrog F1 thiab LcrV muab kev tiv thaiv sai tiv thaiv aerosol kev sib tw nrog Y. pestis. Qhov nce ntxiv ntawm cov tshuaj tiv thaiv LcrV IgG titers tau pom nyob rau Hnub 8 thiab 9 qhia tias cov tshuaj tiv thaiv kab mob muaj zog heev tau qhib los ntawm LcrV thaum ntxov tom qab txhaj tshuaj. Qhov tsis muaj cov tshuaj tiv thaiv-LcrV IgG3 hauv cov ntshav, lawv cov kinetics sib txawv, thiab cov qib qis ntawm cov tshuaj tiv thaiv LcrV IgG pom nyob rau hauv cov kua hauv lub ntsws qhia tau hais tias cov tshuaj tiv thaiv tsis sib haum tau qhib los ntawm F1 thiab LcrV antigens, ob qho tib si feem ntau. tej zaum yuav pab txhawb rau qhov kev tshem tawm sai ntawm cov lus teb tiv thaiv (Daim duab 3C).
Zoo ib yam li peb cov kev soj ntsuam yav dhau los hauv tus qauv bubonic plague nas, muaj peev xwm ua kom muaj kev tiv thaiv kab mob sai sai tiv thaiv tus kab mob plague nyob ntawm cov qauv polymeric ntawm F1 antigen (Daim duab 3). Qhov kev soj ntsuam no qhia tau hais tias tus neeg sib tw tshaj plaws los tiv thaiv kab mob plague subunit tshuaj tiv thaiv, uas muaj monomeric F1 thiab LcrV raws li fusion protein [35,36], tsis xav tias yuav muab qhov pib sai ntawm kev tiv thaiv kab mob pneumonic plague; Txawm li cas los xij, qhov kev xav no yuav tsum tau tshuaj xyuas kev sim. Cov lus teb serological tsim los ntawm LcrV, txawm tias qeeb dua li ntawm polyF1 (Daim duab 2), tseem tso cai rau kev tiv thaiv kev hloov pauv sai uas tiv thaiv qhov ua rau tuag taus ntawm tus kab mob plague. Qhov no kuj ceev serological teb tej zaum stemmed los ntawm lub peev xwm ntawm LcrV antigen los tsim dimers los yog tetramers nyob rau hauv cov kev daws, raws li tau pom nyob rau hauv yav dhau los kev tshawb fawb [37,38] thiab peb cov ntaub ntawv tsis tau luam tawm. Nyob rau hauv lub teeb ntawm peb cov kev tshawb pom ntawm cov nyhuv ntawm cov qauv multimeric ntawm F1 nyob rau hauv expediting lub tiam ntawm ib tug humoral tiv thaiv kab mob, recombinant engineering ntawm LcrV protein uas enables multimerization mus rau ib tug ntau dua yuav ua rau kom cov lus teb. Raws li qhov kev xav no, nws tsim nyog sau cia cov ntaub ntawv tsis ntev los no tau sau tseg tias microcrystals muaj F1 thiab LcrV muaj kev tiv thaiv ntau dua li cov tshuaj tiv thaiv zoo sib xws uas muaj cov antigens hauv daim ntawv soluble [39]. Qhov kev soj ntsuam no qhia tau hais tias nce qhov ceev ntawm cov antigens, uas tshwm sim hauv F1 polymer, tuaj yeem txhim kho thiab muaj peev xwm ua kom muaj kev tiv thaiv kev lom zem.
Ntxiv rau nws lub peev xwm los txhawb kev tiv thaiv kev tiv thaiv sai, hauv kev sim hais txog lub neej ntev ntawm lub xeev tiv thaiv, kev txhaj tshuaj ib zaug nrog polymeric F1 tau tsim muaj kev ruaj khov thiab zoo li IgG titers dua li nrog monomeric F1 (Daim duab 4). Txawm li cas los xij, kev txhaj tshuaj nrog polyF1 ib leeg tsuas yog ib feem ntawm kev tiv thaiv kab mob pneumonic. Ntawm qhov kev ceeb toom, qhov tshwj xeeb tiv thaiv F1 IgG titers ntsuas hauv cov nas ib leeg tsis zoo cuam tshuam nrog lawv lub peev xwm kom muaj sia nyob qhov kev sib tw (Daim duab 5B). Kev txhaj tshuaj ntawm cov nas nrog kev sib xyaw ua ke ntawm txhua daim ntawv F1 ua ke nrog LcrV tsim muaj kev tiv thaiv ntau dua (Daim duab 5). Cov kev tshawb pom no tau ua raws li cov kev tshawb fawb yav dhau los uas tau pom tias kev txhaj tshuaj tiv thaiv kab mob tua tag nrho ntawm tes (KWC), uas ua rau cov tshuaj tiv thaiv-F1 IgG tab sis tsis yog los tiv thaiv LcrV IgG titers, tsis muaj txiaj ntsig hauv kev tiv thaiv kab mob pneumonic plague [13,40] .
Thaum, hauv txoj kev tshawb fawb txog kev ua neej ntev, polyF1 tsuas yog muab qee qhov kev tiv thaiv kab mob lig, cov protein no tau pom tias muaj peev xwm tiv thaiv cov nas sai sai tom qab txhaj tshuaj tiv thaiv, qhia txog kev koom tes ntawm kev tiv thaiv kab mob luv luv uas ua rau kev tshem tawm cov kab mob sai sai. kev sim tshuaj tiv thaiv kab mob. Peb tsis ntev los no tau pom tias kev txhaj tshuaj tiv thaiv kab mob Y. pestis strain EV76 ua rau muaj kev tiv thaiv kev noj qab haus huv uas tshem tawm cov tshuaj tiv thaiv kab mob siderophore-mediated virulence mechanisms ntawm cov kab mob sib tw rau cov hlau ions muaj nyob hauv tus tswv tsev, pab txhawb qhov pib sai ntawm kev tiv thaiv kab mob plague [ 41] ib. Elucidation ntawm kev txhawb nqa lub neej luv luv uas sib koom ua ke nrog cov tshuaj tiv thaiv-F1 humoral tiv thaiv kab mob tuaj yeem pab txhim kho cov tshuaj tiv thaiv zoo tiv thaiv kab mob plague nrog rau lwm yam kab mob tuag taus.
Cov khoom siv ntxiv:
Cov ntaub ntawv txhawb nqa hauv qab no tuaj yeem rub tawm ntawm https://https://www.mdpi.com/article/10.3390/vaccines11030581/s1, Daim duab S1: Tus cwj pwm ntawm tus kab mob plague nram qab no inoculation ntawm Y. pestis Kim53. Daim duab S2: Isotype characterization ntawm anti-F1 thiab anti-LcrV cov tshuaj tiv thaiv nyob rau hauv cov tshuaj tiv thaiv nas. Daim duab S3: Lub neej ntev ntawm cov lus teb serological thiab ciaj sia ntawm txiv neej nas tom qab txhaj tshuaj ib zaug nrog monomeric F1 thiab polymeric F1 ib leeg lossis nrog LcrV.
Tus sau kev koom tes:
Conceptualization, EM, thiab YL; Cov ntaub ntawv curation, YL; Kev txheeb xyuas, YL; Kev Tshawb Fawb, MA, AT, DG, YV, AZ, thiab YL; Methodology, YL; Resources, TH, thiab AM; Kev saib xyuas, EM; Kev Sau Ntawv—Cov ntawv sau qub, EM, thiab YL; Kev Sau Ntawv—Saib xyuas thiab kho, TC, EM, thiab YL Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:
Cov kev tshawb fawb no tau txais nyiaj los ntawm Israel lub koom haum rau Kev Tshawb Fawb Txog Kev Tshawb Fawb Txog Kev Tshawb Fawb, nyiaj pub dawb SB/07.
Institutional Review Board Statement:
Tsis siv tau.
Cov Lus Qhia Txog Kev Pom Zoo:
Tsis siv tau.
Cov ntaub ntawv muaj nyob:
Cov ntaub ntawv nthuav tawm hauv qhov kev tshawb fawb no muaj nyob rau ntawm kev thov los ntawm cov kws sau ntawv sib xws.
Kev tsis sib haum xeeb ntawm kev txaus siab:
Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab.
Cov ntaub ntawv
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