Diversity Thiab Evolution Of Computationally Predicted T Cell Epitopes Against Human Respiratory Syncytial Virus
Dec 05, 2023
Abstract
Human respiratory syncytial virus (RSV) yog ib qho tseem ceeb ua rau tus kab mob ua pa qis. Txawm tias ntau tshaj 60 xyoo ntawm kev tshawb fawb, tsis muaj cov tshuaj tiv thaiv muaj ntawv tso cai. Thaum B cell teb yog qhov tseem ceeb rau kev tsim tshuaj tiv thaiv, T cell epitope profile ntawm RSV kuj tseem ceeb rau kev tsim tshuaj tiv thaiv. Ntawm no, peb kwv yees kwv yees putative T cell epitopes nyob rau hauv Fusion protein (F) thiab Glycoprotein (G) ntawm RSV qus circulating hom los ntawm kev kwv yees Major Histocompatibility Complex (MHC) chav kawm I thiab chav kawm II binding affinity. Peb txwv peb qhov kev xam pom rau kev khaws cia cov epitopes nyob rau hauv ob qho tib si F thiab G cov proteins uas tau sim validated. Peb siv multidimensional scaling (MDS) los tsim T cell epitope toj roob hauv pes los tshawb xyuas qhov sib txawv thiab kev hloov pauv ntawm T cell profiles hla ntau hom RSV. Peb pom cov kab mob RSV tau muab faib ua peb pawg RSV-A thiab ob pawg RSV-B ntawm T epitope toj roob hauv pes. Cov pawg no sawv cev rau cov kab mob RSV sib txawv uas muaj peev xwm sib txawv ntawm cov kab mob immunogenic. Tsis tas li ntawd, peb cov txiaj ntsig tau pom ntau dua ntawm F protein T cell epitope cov ntsiab lus kev txuag ntawm cov kab mob sib kis tsis ntev los no, thaum G protein T cell epitope cov ntsiab lus tau txo qis. Qhov tseem ceeb, peb cov txiaj ntsig tau qhia tias RSV-A thiab RSV-B muaj cov qauv sib txawv ntawm epitope drift thiab hloov pauv thiab cov tshuaj tiv thaiv RSV-B yuav xav tau kev hloov kho ntau zaus. Peb txoj kev tshawb fawb muab cov txheej txheem tshiab los kawm RSV T cell epitope evolution. Kev nkag siab txog cov qauv ntawm T cell epitope kev txuag thiab kev hloov pauv yuav muaj txiaj ntsig zoo rau kev tsim tshuaj tiv thaiv thiab kev ntsuas.
Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob
Author Summary
Cov kab mob ua pa qis los ntawm tib neeg ua pa syncytial virus (RSV) yog ib qho kev sib tw kev noj qab haus huv thoob ntiaj teb. B cell epitope tiv thaiv kab mob yog qhov tseem ceeb ntawm cov tshuaj tiv thaiv RSV thiab kev txhim kho kho. Txawm li cas los xij, T cell epitope-induced immunity plays lub luag haujlwm tseem ceeb hauv kev daws teeb meem ntawm tus kab mob RSV. Thaum RSV muaj ntau haiv neeg tau tshaj tawm thoob plaws, qee qhov kev tshawb fawb tsom mus rau RSV T cell epitope ntau haiv neeg, uas tuaj yeem cuam tshuam cov tshuaj tiv thaiv zoo. Ntawm no, peb siv kev kwv yees kwv yees T cell epitope profiles ntawm circulating strains los ua tus yam ntxwv ntawm ntau haiv neeg thiab evolution ntawm T cell epitope ntawm RSV A thiab B. Peb systematically ntsuam xyuas lub T cell epitope profile ntawm RSV F thiab G proteins. Peb muab T cell epitope toj roob hauv pes visualization uas qhia tau hais tias kev sib koom ua ke ntawm peb pawg RSV-A thiab ob pawg RSV-B, qhia txog qhov sib txawv ntawm T cell tiv thaiv. Tsis tas li ntawd, peb txoj kev tshawb fawb qhia tau hais tias sib txawv ntawm F thiab G protein T cell epitope cov ntsiab lus kev txuag, uas tej zaum yuav yog ib qho tseem ceeb rau kev cuam tshuam nrog lub sij hawm ntawm kev tiv thaiv tshuaj tiv thaiv. Txoj kev tshawb no muab cov txheej txheem tshiab los kawm txog RSV T cell epitope evolution, infer RSV T cell tiv thaiv ntawm cov pejxeem, thiab saib xyuas cov tshuaj tiv thaiv RSV.
Taw qhia
Human respiratory syncytial virus (RSV) yog tus kab mob tsis zoo-strand RNA uas tau muab cais tawm hauvOrthopneumovirusgenus ntawm tsev neegPneumoviridae. Nws yog ib qho tseem ceeb ntawm cov kab mob ua pa qis hauv cov me nyuam mos, cov neeg tsis muaj zog tiv thaiv kab mob, thiab cov neeg laus, uas ua rau muaj kev sib kis txhua xyoo thoob ntiaj teb [1]. Ib leeg-stranded RNA genome ntawm RSV yog kwv yees li 15.2 kb thiab encodes 11 kab mob proteins [2]. Fusion (F) thiab Glycoprotein (G) cov proteins yog ob qhov loj ntawm cov proteins [3]. F protein feem ntau xav tias yuav txuag tau thiab yog li nws yog qhov tseem ceeb ntawm feem ntau cov tshuaj tiv thaiv RSV tam sim no. Txawm hais tias G protein yog qhov sib txawv heev, nws qhov kev pab cuam rau cov kab mob pathogenesis thiab nws lub luag haujlwm hauv biology ntawm tus kab mob qhia tias nws tuaj yeem ua tau zoo RSV tshuaj tiv thaiv antigen [4]. Txawm hais tias muaj lub nra hnyav ntawm tus kab mob RSV thoob ntiaj teb, tsis muaj cov tshuaj tiv thaiv muaj ntawv tso cai. Qhov kev pom zoo nkaus xwb yog kev tiv thaiv kab mob tiv thaiv kab mob tiv thaiv kab mob nrog palivizumab, uas yog ua tiav los ntawm kev tswj hwm cov tshuaj tiv thaiv kab mob monoclonal (mAb) rau ib pab pawg me nyuam mos uas muaj hnub nyoog qis dua 24 lub hlis thiab kev kho mob yuav tsum tau rov ua dua txhua hli thaum lub caij RSV vim qhov cuam tshuam. luv ib nrab-lub neej ntawm cov tshuaj tiv thaiv [5,6]. Vim yog tus nqi siab ntawm kev kho mob monoclonal antibody, qhov kev cuam tshuam no txwv rau cov menyuam mos uas muaj kev pheej hmoo siab thiab feem ntau tsis muaj nyob hauv cov teb chaws tsim. Ib qho tshuaj tiv thaiv RSV yog qhov tseem ceeb hauv ntiaj teb kev noj qab haus huv tseem ceeb, thiab nws yog qhov yuav tsum muaj cov tswv yim sib txawv rau ntau pawg uas muaj kev pheej hmoo siab.
cistanche cov txiaj ntsig-ua kom muaj zog tiv thaiv kab mob
Ntau pab pawg tshawb fawb tau ua haujlwm ntawm kev tsim cov tshuaj tiv thaiv RSV txij li nws qhov kev sib cais thiab tus yam ntxwv hauv xyoo 1956 [7,8]. Txawm li cas los xij, kev txhaj tshuaj nrog formalin-inactivated, alum-precipitated RSV (FI-RSV) tshuaj tiv thaiv hauv RSV-naïve cov me nyuam mos thiab cov me nyuam yaus, ua rau muaj kev txhim kho cov tshuaj tiv thaiv kab mob (VED) uas cuam tshuam kev tsim tshuaj tiv thaiv rau ntau xyoo los ua raws [9 ]. Ntau qhov kev tshawb fawb tau ua los piav qhia qhov tshwm sim tsis zoo no. Nws zoo li tias formalin fixation coj mus rau ib qho tshuaj tiv thaiv uas feem ntau nthuav tawm tom qab kev sib xyaw ua ke ntawm RSV F protein, uas ua rau muaj ntau dhau ntawm cov tshuaj tiv thaiv uas tsis yog nruab nrab thiab lub cev tiv thaiv kab mob [10–12]. Lwm cov kev tshawb fawb tau qhia tias qhov tsis zoo ntawm T cell teb nrog Th2 skewing [13,14], nrog rau kev tso tawm ntxiv hauv lub ntsws, pab txhawb kev txhim kho neutrophil recruitment [12]. Kev tsim kho tsis ntev los no, suav nrog kev daws teeb meem ntawm F protein [15] thiab kev txhim kho ntawm RSV nas qauv [16] tau pab txhawb rau ntau tus neeg siv tshuaj tiv thaiv nrog cov qauv tsim tshiab thiab cov qauv tam sim no hauv kev sim tshuaj [3,17,18]. Thaum tam sim no feem ntau cov tswv yim txhaj tshuaj tiv thaiv RSV tsom rau B-cell-induced neutralization tiv thaiv kab mob, T-cell tiv thaiv kuj ua lub luag haujlwm tseem ceeb hauv kev daws teeb meem ntawm tus kab mob thiab yog qhov tseem ceeb rau kev tsim tshuaj tiv thaiv RSV [17,18]. Thaum RSV kab mob ntawm cov hlab ntsws qis tau tsim, CD8 T hlwb ua haujlwm tseem ceeb hauv kev tshem tawm cov kab mob thiab CD4 tus pab T hlwb tuaj yeem ua rau lub cev tiv thaiv kab mob thiab txhawb nqa B hlwb los tsim cov tshuaj tiv thaiv. Txawm li cas los xij, Th2- cov lus teb tsis txaus ntseeg tau cuam tshuam nrog cov qauv tsiaj ntawm RSV VED, thiab kev ntsuas ntawm Th1 thiab Th2 cov lus teb yog suav tias yog qhov tseem ceeb rau kev kwv yees kev nyab xeeb ntawm cov neeg sib tw tshuaj tiv thaiv [12]. Yog li ntawd, induction ntawm lub cev sib npaug ntawm lub cev tiv thaiv kab mob los ntawm kev txhaj tshuaj tiv thaiv yuav txhawb nqa RSV tshem tawm, tab sis yuav tsum tau ceev faj kom tsis txhob muaj peev xwm tiv thaiv kab mob. Ua ke, kev soj ntsuam ze dua ntawm T cell tiv thaiv kab mob thiab kab mob kab mob uas ua rau T cell teb yog xav tau rau kev tsim tshuaj tiv thaiv RSV.
Tib neeg txoj kev ua pa syncytial tus kab mob muaj ib tug complex ncig qauv nyob rau hauv tib neeg cov pejxeem. Hauv ob pawg antigenic, RSV-A thiab RSV-B, cov genotypes sib txawv tuaj yeem sib koom ua ke hauv tib lub zej zog, thaum tshiab RSV genotypes uas muaj ntau hom genomic tuaj yeem tshwm sim thiab muaj peev xwm hloov cov genotypes yav dhau los [19]. Hauv xyoo tas los no, ntau qhov kev hloov pauv caj ces hauv RSV tau raug txheeb xyuas, suav nrog 72-nucleotide (nt) duplication (ON genotype) hauv RSV-A G noob thiab lwm yam nrog 60-nt duplication (BA genotype ) hauv RSV-B ntawm thaj chaw zoo sib xws [20]. Kev soj ntsuam RSV genetic ntau haiv neeg tau tsa ib lo lus nug txog seb nws puas tsim nyog rau cov tshuaj tiv thaiv RSV kom suav nrog ntau hom kab sib txawv kom ua tau zoo. Cov tshuaj tiv thaiv RSV tam sim no feem ntau yog ua raws li RSV A2 qhov chaw kuaj mob, uas yog ib hom kab mob chimeric uas muaj nyob rau hauv subtype A [21]. Thaum cov kev kho mob no tuav cov lus cog tseg, muaj peev xwm ntawm cov kab mob viral tsim kev hloov pauv. Piv txwv li, palivizumab-resistant hom tau raug cais tawm ntawm ob qho tib si RSV nas qauv thiab tib neeg [17,22]. Ntau cov ntaub ntawv pov thawj kuj qhia tias kev hloov pauv ntawm cov tshuaj tiv thaiv kab mob tuaj yeem ua lub luag haujlwm hauv lub peev xwm ntawm RSV kom dim ntawm lub cev tiv thaiv kab mob thiab tsim kab mob [23]. Txawm tias muaj kev txuag T cell epitopes hauv cov tshuaj tiv thaiv RSV yuav tsis muaj kev tiv thaiv tag nrho ntawm kev tiv thaiv kab mob thaum tsis muaj cov tshuaj tiv thaiv kab mob tiv thaiv kab mob, kev txuag T cell epitopes hauv cov tshuaj tiv thaiv kuj tseem yuav txo tau qhov mob hnyav thiab txwv tsis pub kis tus kab mob. Txawm li cas los xij, amino-acid variation ntawm T cell epitope thiab qhov muaj peev xwm tshwm sim ntawm T cell epitopes tshiab ntawm RSV circulating hom tsis ntev los no tau tshaj tawm [24], thiab xav tau kev tshawb fawb ntxiv los qhia txog qhov cuam tshuam ntawm amino acid variations ntawm T cell paub. . Yog li ntawd, tus cwj pwm ntawm T cell epitope profiles thoob plaws ntau hom yog ib qho tseem ceeb heev kom nkag siab txog RSV evolution thiab tuaj yeem yog qhov tseem ceeb rau kev tsim tshuaj tiv thaiv RSV.
cistanche cog-nce kev tiv thaiv kab mob
Nyem qhov no mus saib Cistanche Enhance Immunity khoom
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Hauv txoj kev tshawb no, peb siv cov txheej txheem immunoinformatic uas tau siv hauv iVAX cov cuab yeej [25] los kwv yees T cell epitopes hauv RSV hla ntau hom kab mob nrog rau kev tsom mus rau ob qhov loj ntawm cov proteins F thiab G. Nrog rau kev tsom xam ntawm cov ntaub ntawv qhia ntxaws, peb. soj ntsuam cov kab mob tshwj xeeb T cell epitope profile ntawm RSV. Peb kuj tsim cov kab ke raws li T cell epitope toj roob hauv pes raws li epitope cov ntsiab lus sib piv nyob rau hauv ntau hom thiab ntxiv correlates RSV T cell tiv thaiv kev hloov pauv nrog tus kab mob evolution. Qhov kev faib ua feem ntawm tus ntoo khaub lig-conserved T cell epitope cov ntsiab lus ntawm cov tshuaj tiv thaiv tus neeg sib tw hom kab mob uas tau tsim ua ntej thiab RSV cov kab mob sib kis nrog ntau xyoo kev sib cais thiab qhov chaw kuj tau suav. Cov kev tshuaj ntsuam no tuaj yeem pab nkag siab txog RSV T cell tiv thaiv kab mob sib txawv thiab pab txhawb rau kev tsim tshuaj tiv thaiv tam sim no.
Cov txiaj ntsig
Kev faib tawm ntawm T cell epitopes hauv RSV nto proteins
Peb tau soj ntsuam T cell immunogenic muaj peev xwm hla RSV cov protein ntau los ntawm kev tshuaj xyuas 9 thaj chaw seem los kwv yees qhov kev sib txuas ntawm MHC chav kawm I thiab chav kawm II molecules (Fig 1). Lub epitope ntom ntom ntawm RSV nto proteins tau raug soj ntsuam siv cov qhab nia zoo li qub epitope ntom ntom, uas yog xam los ntawm kev suav nrog kev kwv yees peptide-MHC binding qhab nia hla cov protein thiab normalizing nws nrog cov protein ntev. Cov qhab nia rau cov proteins uas tau tsim los ntawm qhov raug teeb tsa rau xoom thiab cov tshuaj tiv thaiv antigens feem ntau tau qhab nia saum toj no +20 ntawm qhov ntsuas no [25]. F protein muaj qhov ua kom tus nqi siab dua qhab nia ntau dua +20}} Ii} Tsom phaj tsom iav, qhia tias muaj peev xwm tiv thaiv kev tiv thaiv kev tiv thaiv kev tiv thaiv, muaj peev xwm Qhov no sib piv nrog qis G protein hauv chav kawm I thiab chav kawm II epitope density protein cov qhab nia rau ob hom RSV subtypes. Chav kawm I epitope density qhab nia ntawm G protein ntau dua +10 nyob rau hauv ob qho tib si subtypes tab sis chav kawm II ceev yog qis dua qhov kev cia siab nyob rau hauv kev tsom xam ntawm RSV-B (Fig 1A). Cov txiaj ntsig no qhia tau tias RSV cov proteins saum npoo zoo li yuav muaj peev xwm los txhawb T hlwb uas xav tau kev tiv thaiv kev tiv thaiv. Tom qab ntawd peb tau tshawb xyuas qhov kev faib tawm ntawm T cell immunogenicity thoob plaws cov proteins thiab pom tias muaj cov cheeb tsam uas muaj T cell immunogenic muaj peev xwm (Fig 1B). Kev faib tawm ntawm T cell immunogenicity ntawm F protein tau pom zoo rau nws cov qauv protein thiab sib tshooj ntawm thaj tsam protein ntau uas muaj T cell tiv thaiv kab mob siab thiab cov tshuaj tiv thaiv kab mob tsis zoo tau pom ntawm qhov chaw antigenic F thiab site II.
Fig 1. T cell immunogenic muaj peev xwm rau RSV nto proteins raws li MHC binding kwv yees
Kab mob tshwj xeeb T cell epitope profiles
Peb mam li txuas ntxiv T cell epitope kwv yees los ntawm RSV tus neeg sawv cev rau ntau hom tsiaj qus. Kev faib tawm thiab ntau haiv neeg ntawm T cell epitopes thoob plaws cov kab mob sib txawv tau piav qhia hauv cov duab tshav kub nrog rau cov sijhawm sib xws (S1 thiab S2 Figs). Ob leeg F thiab G cov proteins muaj cov epitopes uas tau khaws cia thoob plaws tag nrho cov kab mob RSV hauv yuav luag 100% ntawm cov qauv cais tawm, qhia tias lawv tuaj yeem ua haujlwm zoo T cell epitope cov neeg sib tw rau kev tsim tshuaj tiv thaiv. Hauv qhov sib piv, qee qhov epitopes tau hloov pauv hauv cov kab mob uas tau xaiv, thiab cov epitopes uas tsuas yog tshwm sim hauv qee qhov clades hauv phylogeny tuaj yeem txhais tau tias yog clade-tshwj xeeb "tus ntiv tes".
G gene duplication txheej xwm nyob rau hauv RSV, uas yog tshwj xeeb gene kos npe, tuaj yeem hloov txoj hauj lwm ntawm epitopes (qhov chaw sib txawv tab sis cov amino acids ntawm epitopes zoo ib yam rau G protein cais tsis muaj duplication) lossis ua rau qhov tshwm sim ntawm cov epitopes tshiab. Ob chav kawm tshiab I epitopes, (no. 31 thiab no. 40 hauv S2A Fig), tau pom nyob rau hauv RSV-A hom uas muaj G gene duplication. Tsis tas li ntawd, ib qho kev tshwm sim hauv chav kawm II epitope (no. 25 hauv S2A Fig) tau pom nyob rau hauv RSV-A ib ntus uas muaj G gene duplication, uas yog kev hloov ntawm ib qho epitope (no. 24) uas tau pom nyob rau hauv lwm hom. Los ntawm RSV-B hom uas muaj G gene duplication tshwm sim, peb kuj tau pom ntau yam kab mob tshwj xeeb hauv chav kawm IT cell epitopes, uas yog tshwm sim los ntawm 2-amino acid (aa) deletion (aa157 thiab aa158) hauv cov hom no. ntawm ncaj qha vim yog 60-nt duplication tshwm sim. RSV-B G proteins uas muaj qhov kev tshwm sim duplication muaj ntau yam tshiab epitopes (no. 22, 23, 26, 28, 30, 37) tab sis tsis muaj ob peb epitopes (no. 24, 25, 27, 29, 31, 38) uas tau txheeb xyuas hauv lwm hom kab mob (S2B Fig). Txhawm rau txiav txim siab ntxiv seb puas muaj kev kwv yees kwv yees T cell epitopes nrog siab MHC binding peev xwm yog immunogenic, peb siv JanusMatrix [27] algorithm los txheeb xyuas T cell epitopes uas zoo li yuav hla-kev txuag nrog tib neeg peptides thiab yog li zam los ntawm lub cev tiv thaiv kab mob. . Raws li qhov kev tshuaj ntsuam no, 6.45% ntawm putative class I epitopes thiab 1.12% ntawm putative class II epitopes ntawm RSV loj nto proteins yog cross-conserved nrog tib neeg proteome-derived epitopes ntawm T cell receptor (TCR)-facing residues. Raws li cov peptides muaj qhov zoo sib xws ntawm HLA kev nyiam kev sib khi uas muaj nyob hauv tib neeg cov proteins (S3 Fig), lawv thiaj li xav tias tsis yog immunogenic. Tom qab tsis suav nrog qhov siab-JanusMatrix cov qhab nia epitopes tau teev tseg saum toj no, peb tuaj yeem txheeb xyuas T cell epitopes uas tau khaws cia hauv ntau dua 60% ntawm cov kab mob RSV tam sim no. Peb tau tshawb xyuas IEDB epitope database los txiav txim seb cov epitopes no puas muaj feem xyuam rau kev sim siv tau RSV T cell epitopes lossis HLA ligands (Table A hauv S1 Text). Kev txuag RSV T cell epitope ib ntus uas tej zaum yuav yog ib qho tseem ceeb rau kev tsim tshuaj tiv thaiv yav tom ntej yog qhia hauv Cov Lus 1 thiab 2 (Tables B thiab C hauv S1 Text).
Table 1. Kev sim ua pov thawj tias MHC chav kawm I epitopes peptides hauv RSV cov protein loj
Kwv yees RSV T cell epitope toj roob hauv pes
To investigate the evolution of RSV on T cell immunity profiles, we use a multidimensional scaling (MDS) approach to visualize the T cell immunity profile of multiple RSV strains on a landscape. We performed a T cell epitope content pairwise comparison between RSV strains using in silico predicted peptide-HLA allele binding affinity. The pairwise T-cell epitope distances were then calculated using the algorithm reported in this study (Eq 1). We then applied a multidimensional scaling (MDS) approach using these estimated pair-wise T epitope distances to map RSV strains to a landscape to characterize their T-cell immunity profile. We found both class I and class II T cell immunity profiles of F and G proteins of different RSV strains were clustered into groups on this T cell epitope landscape (S4 Fig). Combining the class I and class II T-cell epitope binding profiles, RSV-A major surface protein isolates can be divided into three clusters and RSV-B major surface protein isolates can be divided into two clusters (Figs 2 and S5). We observe that the G gene sequence isolates that contain 72-nt (RSV-A) or 60-nt (RSV-B) duplications clustered together with other sequences instead of forming isolated groups. To further investigate the T cell epitope diversity, we correlated this clustering pattern with the phylogenetic histories (Fig 2B). The phylogenetic tree topologies of the RSV-A F gene and the G gene are similar. The F gene cluster 1 is paraphyletic, while clusters 2 and 3 are monophyletic. Cluster 1 is the closest to the ancestral sequence and mapping this group onto the phylogeny shows that this cluster has a basal relationship with clusters 2 and 3 indicating that the phylogenetic divergence occurred prior to epitope drift. The RSV-B F and G gene genealogies are very different. In particular, the RSV-B F gene topologies are indicative of strong immune selection, similar to observed human influenza A virus or within host HIV phylogenies [28]. In contrast, the RSV-B G gene phylogeny shows the co-circulation of multiple lineages, though this could reflect the sequencing bias of G genes (Fig 2B). We then calculated the T-cell epitope immune distance of each strain from a reconstructed ancestral sequence (Fig 2C). These distances were then plotted against the year of isolation and colored according to the cluster identified in Fig 2A. RSV-A shows that multiple predicted immune phenotypes co-circulate and persist for long periods (>2 xyoo). Kev soj ntsuam ntawm RSV-B qhia txog kev hloov pauv ntawm qhov kwv yees tiv thaiv kab mob phenotypes nrog lub sijhawm luv ntawm kev sib koom ua ke (<5 years) for F and G protein T cell epitopes. The limited periods of co-circulation are again consistent with phenotype patterns observed for viruses under strong immune selection (e.g. H3N2 influenza A virus) [29,30]. In contrast, genetic distances from the reconstructed ancestral sequence plotted against year of isolation show patterns typical of gradual genetic drift, except in the G gene where a 72-nt and 60-nt insertion is present (Fig 2D). Taken together, these results suggest that genetic and predicted T-cell epitope immune diversity are different and may be an important factor to consider when evaluating RSV vaccine efficacy.
Table 2. Kev sim ua pov thawj tau txais kev pov hwm MHC chav kawm II epitopes peptides hauv RSV cov protein loj
Daim duab 2. Predicted T cell epitope toj roob hauv pes thiab genetic evolution ntawm RSV nto proteins
Muaj ntau txoj hauv kev muaj los kwv yees T cell epitopes [31], uas yuav ua rau muaj qhov sib txawv ntawm cov kev tsim kho dua tshiab yog tias muaj kev tsis ncaj ncees hauv txoj kev kwv yees. Peb tau siv NetMHCpan txoj kev [32] los kwv yees T cell epitopes thiab ua tib lub toj roob hauv pes tsim kho siv MHC chav kawm kuv khi kev kwv yees rau RSV-A F protein. Peb qhov kev soj ntsuam tau pom cov qauv sib xws ntawm RSV T epitope profile ntawm toj roob hauv pes tsis hais txog T cell epitope txoj kev kwv yees (S7 Fig).
Daim duab 3. Kev soj ntsuam ntawm yav tas los siv cov tshuaj tiv thaiv RSV cov neeg sib tw nrog T cell epitope cov ntsiab lus ntawm cov kab mob sib kis
Kev soj ntsuam ntawm cov tshuaj tiv thaiv tus kab mob nrog T cell epitope cov ntsiab lus
T cell epitopes that are similar between vaccine strains and wild strains (cross-conserved T epitopes, which are defined as epitopes that share identical T cell receptor-facing residues and are restricted by the same alleles [33]) may be responsible for the T cell immune protection of the vaccine. To quantitatively evaluate whether it might be necessary to include multiple RSV strains to prepare an effective vaccine, two live attenuated RSV strains that are previously considered as vaccine candidates, CP248, a recombinant virus that belongs to subtype A, and CP52, which is a recombinant RSV-B strain, were included in our analysis and we evaluated their T cell epitope conservation with different RSV wild-type strains. We calculated the average proportion of cross-conserved T cell epitope content between the selected vaccine strains and wild-circulating strains from different isolation years and WHO regional groups (Figs 3 and S8). Different proportions of cross-conserved T cell epitope content against isolates from two different subtypes, A and B, were observed in both the F and G protein analyses. In the comparison of the vaccine strains and wild strains belonging to the same subtype, the proportion of cross-conserved T cell epitope in RSV F protein is relatively stable in different groups, all are higher than 78% for RSV-A and higher than 85% for RSV-B. In contrast, changes in the proportion of cross-conserved T cell epitopes were detected among groups within the same RSV subtype, especially in different temporal groups in the G protein analysis (Fig 3). Vaccine strain CP248 appears to have a relatively higher proportion of cross-conserved T cell epitopes within G protein when compared to the RSV-A strains that were isolated before 1991 (>70%) thiab qib qis ntawm kev txuag tiv thaiv cov kab mob uas tsis ntev los no. Ib qho kev txo qis hauv T cell epitope kev txuag nrog lub sijhawm tau txheeb xyuas rau cov tshuaj tiv thaiv kab mob CP52 ntawm cov kab mob RSV-B.
Kev sib tham
Txawm hais tias ob qho tib si CD4 thiab CD8 T hlwb pab txhawb kev tiv thaiv kab mob RSV-induced tom qab thawj kab mob [16,34], T cell epitopes tau txais kev saib xyuas tsawg hauv RSV kev tshawb fawb. Peb pom tau hais tias RSV cov proteins saum npoo zoo li muaj peev xwm tseem ceeb los tsav T cell tiv thaiv kev siv cov kev suav nrog, raws li lawv cov qhab nias T cell epitope ntom ntom raws li tau txiav txim los ntawm MHC molecular binding kev kwv yees. Qhov tseem ceeb tshaj plaws t cell poritope ceev yuav ua rau f protein lub hom phiaj zoo rau cov tshuaj tiv thaiv RSV. Ntxiv nrog rau kev tsom xam ntawm T cell epitope ceev thiab kev faib tawm hauv RSV cov protein ntau saum npoo, peb kuj tau pom cov kab mob tshwj xeeb hloov pauv hauv T cell epitope cov ntsiab lus. Txawm hais tias RSV F protein tau ntseeg tias tau txais txiaj ntsig zoo, kev hloov pauv ntawm epitope tau pom nyob thoob plaws cov kab sib txawv hauv F protein, qhia tias kev kawm cov kab mob tshwj xeeb T cell epitopes hauv RSV tuaj yeem muab kev nkag siab txog qhov cuam tshuam ntawm kev tiv thaiv kab mob ntawm cov kab mob sib txawv thiab kev pheej hmoo. . Nyob rau hauv sib piv rau cov conserved F protein, RSV G protein tau tshaj tawm tias muaj kev hloov pauv, peb tseem pom muaj peev xwm khaws cia T cell epitopes thoob plaws ntau hom, uas qhia tau hais tias muaj kev txaus siab rau G protein conserved domain raws li cov tshuaj tiv thaiv lub hom phiaj ntawm T cell tiv thaiv kab mob. . Thaum xav tau kev sim ua pov thawj, qhov kev tshuaj ntsuam no qhia txog qhov tseem ceeb ntawm kev nkag siab txog kev txuag pej xeem-theem epitope vim nws tuaj yeem muab kev pom tseem ceeb rau kev tsim cov tshuaj tiv thaiv T cell epitope-tsav tshuaj tiv thaiv kab mob RSV.
Lub hom phiaj tseem ceeb ntawm peb txoj haujlwm yog kev txhim kho cov txheej txheem ua ntu zus los qhia txog kev hloov pauv ntawm T cell tiv thaiv kab mob sib txawv. Ua raws li kev ua haujlwm tseem ceeb yav dhau los uas tau siv MDS txoj hauv kev los qhia txog kev hloov pauv hloov pauv ntawm tus kab mob khaub thuas A tus kab mob tshwm sim los ntawm CD8 T hlwb siv qhov muaj thiab tsis muaj MHC chav kawm I epitopes [35], peb tsim RSV T cell tiv thaiv thaj chaw siv kev tiv thaiv kab mob. tau tsim los ntawm T cell epitope cross-conservation analyses, uas tso cai rau kom pom tau yooj yim thiab intuitive nkag siab txog lub peev xwm rau T cell tiv thaiv kev sib raug zoo ntawm ntau hom. Thaum sib piv thoob plaws hom, peb pom tias T cell epitope cov ntsiab lus ntawm RSV nto proteins los ntawm ntau hom tuaj yeem ua pawg, raws li tau pom zoo rau kev sib raug zoo antigenic qhia hauv lwm cov kab mob [36,37]. Peb cov txiaj ntsig tseem qhia tau hais tias kev sib txuas lus ntawm RSV T cell tiv thaiv pawg thiab lawv cov kev sib raug zoo, nrog cov kab ke hauv tib lub clade feem ntau koom nrog tib lub T cell tiv thaiv pawg. Qhov tseem ceeb, peb kuj saib cov qauv sib txawv ntawm T-cell epitope evolution ntawm RSV cov tsiaj qus piv nrog lawv cov genetic evolution. Peb pom cov kab mob RSV nrog G gene duplications tseem tuaj yeem ua ke nrog cov RSV yav dhau los cais ntawm T cell epitope MDS qhov chaw. Peb cov txiaj ntsig tau qhia txog qhov tseem ceeb ntawm kev hloov pauv T cell epitope hauv RSV.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Peb tau txheeb xyuas qhov kev txuag RSV T cell epitopes hauv txoj kev tshawb no, qee qhov uas twb tau sim siv tau thiab luam tawm hauv IEDB database. Txawm li cas los xij, peb kuj tau txheeb xyuas ob peb lwm qhov khaws cia T-cell epitopes uas tsis tau piav qhia yav dhau los. Cov no yuav muaj txiaj ntsig zoo rau kev tsim tshuaj tiv thaiv, txawm hais tias kev sim ntsuas yuav xav tau. Tsis tas li ntawd, homology ntawm kev xaiv RSV epitopes rau tib neeg peptides qhia tias qee qhov kev kwv yees RSV T cell epitopes yuav raug zam los ntawm tib neeg lub cev tiv thaiv kab mob lossis tuaj yeem ua rau muaj teeb meem cuam tshuam tiv thaiv kab mob tiv thaiv tib neeg cov proteins thaum noj nrog adjuvant [27]. Qee yam ntawm kev tiv thaiv kab mob RSV tsis tau hais los ntawm txoj kev tshawb no. Piv txwv li, neutralizing antibody cov lus teb tam sim no suav tias yog qhov tseem ceeb tshaj plaws ntawm kev tiv thaiv kab mob. Thaum cov tshuaj tiv thaiv kab mob tsis zoo yuav tsis ncaj qha los ntawm T cell epitope-tsav tshuaj tiv thaiv, tus pab (CD4) T cell epitopes yuav tsum tau tsim kom muaj kev sib raug zoo siab, cov tshuaj tiv thaiv tshwj xeeb. Peb kuj tseem nco ntsoov tias peb tau txwv peb txoj kev tsom mus rau ob qhov loj ntawm RSV cov proteins hauv peb qhov kev tshuaj ntsuam tam sim no, tab sis lwm cov RSV cov proteins xws li N, M, lossis M2-2 cov proteins kuj tseem tuaj yeem pab txhawb kev siv tshuaj tiv thaiv [38].
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Cov tshuaj tiv thaiv zoo tiv thaiv kab mob sib txawv yuav tsum muaj T-cell epitopes uas tau txais txiaj ntsig zoo ntawm cov kab mob sib kis [39]. Kev siv tshuaj tiv thaiv tuaj yeem txo qis yog tias T cell epitopes hauv cov tshuaj tiv thaiv tsis sib xws thaum cov kab mob tshiab tshwm sim. Nyob rau hauv txoj kev tshawb no, peb tau siv ib txoj hauv kev immunoinformatic-raws li kev kwv yees tus ntoo khaub lig-conserved T cell epitope cov ntsiab lus ntawm ob nyob attenuated txhaj tshuaj tiv thaiv kab mob thiab RSV circulating qus hom. Peb pom tias muaj qhov tsis tshua muaj feem cuam tshuam ntawm T-cell epitope cov ntsiab lus nrog cov tshuaj tiv thaiv kab mob uas koom nrog ntau pawg antigenic, uas qhia txog kev pheej hmoo ntawm kev siv tib hom kab mob hauv cov tshuaj tiv thaiv RSV. Tsis tas li ntawd, peb tau pom qhov qis dua ntawm kev khaws cia G-protein T cell epitope cov ntsiab lus ntawm cov tshuaj tiv thaiv kab mob thiab cov kab mob tsis ntev los no nyob rau hauv tib pawg antigenic, uas qhia tias suav nrog T cell epitopes los ntawm ntau hom kab mob hauv tib pawg antigenic kuj tseem tuaj yeem ua tau. tseem ceeb rau kev tsim tshuaj tiv thaiv RSV. Txawm hais tias peb tsis tau soj ntsuam qhov kev hloov pauv tseem ceeb hauv kev khaws cia ntawm T cell epitope cov ntsiab lus hauv F protein, peb tsis tuaj yeem txiav txim siab tias qhov kev hloov pauv ntawm F protein yav tom ntej tuaj yeem ua rau cov tshuaj tiv thaiv ib leeg tsis zoo. Peb qhov kev soj ntsuam tam sim no yog ua raws li cov ntaub ntawv txo qis vim qhov hnyav suav nrog lub peev xwm xav tau los ua qhov sib piv cov ntsiab lus epitope. Peb tsim cov ntaub ntawv tus neeg sawv cev no los ntawm randomly subsampling cov ntaub ntawv tiav raws li thaj chaw thaj chaw thiab cov xyoo cais. Peb qhov kev tshawb pom yuav cuam tshuam txog T cell epitope ntau haiv neeg ntawm cov kab mob RSV uas muaj nyob rau hauv pej xeem, txawm li cas los xij, kev soj ntsuam RSV ntxiv yuav raug xav kom tau txais daim duab tag nrho ntawm T cell epitope variability ntawm RSV.
Peb txoj kev tshawb fawb tam sim no raug txwv los ntawm kev tsis muaj kev sim ua pov thawj ntawm T cell epitope kwv yees. Peb tsom mus rau kev kwv yees kwv yees MHC khi los txheeb xyuas T-cell epitopes. Txawm hais tias lub zog ntawm MHC kev khi yog qhov tseem ceeb ntawm kev txiav txim siab peptide's immunogenicity, tab sis tsis txaus rau ib qho qauv los ua immunogenic [40]. Lwm yam cuam tshuam nrog cov kab mob tshwm sim los ntawm T cell tiv thaiv kab mob, xws li tsim nyog antigen-processing [41] thiab T cell receptor recognition [40] tsis raug txiav txim siab hauv txoj kev tshawb no, uas yuav ua rau muaj kev tsis ncaj ncees hauv kev suav nrog T cell epitope toj roob hauv pes. Txawm li cas los xij, cov qauv pom pom ntawm RSV cov protein nyob rau ntawm T cell epitope toj roob hauv pes hauv txoj kev tshawb no qhia txog kev sib txawv ntawm T cell epitopes nyob rau hauv ntau hom. Qhov kev tshawb pom no muab kev nkag siab zoo rau kev hloov pauv ntawm tus kab mob hauv cov yam ntxwv ntawm T-cell tiv thaiv kab mob thiab tuaj yeem pab txhawb rau kev xaiv hom tshuaj tiv thaiv. Zuag qhia tag nrho, txoj kev tshawb no muab kev tsom xam tsom xam ntawm T cell epitopes hauv RSV cov protein loj saum npoo siv cov cuab yeej suav. Peb tau ua tiav T cell epitope kwv yees rau RSV qhia txog kev tiv thaiv kab mob ntawm T cell epitopes hauv RSV cov protein ntau. Txoj kev tshawb no qhia tau hais tias T cell epitope evolution yuav txawv ntawm kev hloov pauv ntawm caj ces thiab muab lub hauv paus rau kev tsim cov tshuaj tiv thaiv epitope-raws li RSV thiab cov txheej txheem tshuaj ntsuam xyuas uas tuaj yeem siv los kho cov tswv yim txhaj tshuaj.
Cov ntaub ntawv
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