SARS-CoV-2 Variant Biology: Immune Escape, Transmission And Fitness
Nov 01, 2023
Nyob rau xyoo 2020, tom qab ncig yuav luag ib xyoos hauv tib neeg cov pej xeem, mob hnyav ua pa nyuaj rau tus mob coronavirus 2 (SARS-CoV-2) tau nthuav tawm cov kauj ruam tseem ceeb hauv kev hloov pauv rau tib neeg. Cov ntawv hloov pauv ntawm SARS-CoV-2 no tau txhim kho tus nqi kis tau tus mob ntsig txog cov kev hloov pauv dhau los thiab raug hu ua 'variants of concern' (VOCs). Tsim Alpha, Beta, Gamma, Delta, thiab Omicron, VOCs tau tshwm sim ntawm nws tus kheej los ntawm ib leeg, thiab nyob rau hauv lem, txhua tus sai sai tau los ua tus tseem ceeb, hauv cheeb tsam los yog thoob ntiaj teb, outcompeting yav dhau los variants. Qhov kev vam meej ntawm txhua tus VOC txheeb ze rau qhov kev hloov pauv yav dhau los tau ua los ntawm kev hloov pauv ntawm lub cev ua haujlwm ntawm tus kab mob thiab, mus rau ntau qib, kev hloov pauv rau tus kab mob antigenicity hais txog lub peev xwm los khiav tawm lub cev tiv thaiv kab mob. Cov kab mob muaj zog ntxiv uas cuam tshuam nrog VOCs yog qhov tshwm sim los ntawm kev sib cuam tshuam ntawm tus kab mob biology hauv cov ntsiab lus ntawm kev hloov tib neeg kev tiv thaiv vim yog kev txhaj tshuaj tiv thaiv thiab kev kis kab mob ua ntej. Hauv qhov Kev Ntsuam Xyuas no, peb sau cov ntaub ntawv hais txog kev sib raug zoo ntawm tus txheeb ze thiab kev tiv thaiv kab mob ntawm SARS-CoV-2 variants, lub luag haujlwm ntawm kev hloov pauv ntawm furin spike cleavage site thiab ntawm cov protein tsis muaj kab mob, qhov tseem ceeb ntawm kev rov ua dua rau tus kab mob ua tiav. , and SARS CoV-2 evolution in the context of T cells, innate immunity, and population immunity. SARS-CoV-2 qhia tau hais tias muaj kev sib raug zoo ntawm cov kab mob antigenicity, kis, thiab virulence, uas muaj qhov cuam tshuam tsis zoo rau future trajectory thiab kab mob lub nra ntawm COVID-19.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Taw qhia
Txij li thaum nws pib tshwm sim hauv Wuhan thaum Lub Kaum Ob Hlis 2019, mob hnyav ua pa nyuaj rau tus mob coronavirus 2 (SARS-CoV-2) tau ua rau ntau dua 641 lab tus neeg mob ntawm COVID-19 thiab ntau dua 6.6 lab tus neeg tuag thaum lub Kaum Ob Hlis 2022. (ref. 1 ). SARS-CoV-2 (nrog rau SARS-CoV, qhov ua rau ntawm SARS) yog ib tug tswv cuab ntawm hom mob hnyav ua pa nyuaj ua rau tus mob coronavirus, tib tus tswv cuab ntawm cov kab mob subgenus, Sarbecovirus, feem ntau pom muaj nyob rau hauv cov kab mob bats2 . Zoo li lwm cov kab mob coronaviruses, SARS-CoV-2 muaj lub RNA genome loj, suav nrog ~ 30,{18}} nucleotides, uas nws qhov kev rov ua dua yog kho los ntawm RNA-dependent RNA polymerase (RdRP) thiab cov ntaub ntawv pov thawj cuam tshuam nrog exoribonuclease (ExoN). ). Qhov no, ua ke nrog cov xwm txheej tsis tu ncua ntawm tus kabmob coronavirus, tau ua rau muaj tus kabmob coronaviruses nrog tus nqi siab ntawm recombination, insertions, deletions, thiab taw tes hloov pauv (txawm hais tias tus nqi qis dua rau lwm cov kab mob RNA vim kev nyeem ntawv pov thawj), raws li yav dhau los tshuaj xyuas 3. Kev vam meej ntawm cov noob caj noob ces hloov tshiab tau tsim, txawm hais tias nws muaj cov txheej txheem stochastic sampling, yuav yog nyob ntawm kev xaiv ntuj; tshwj xeeb, kev xaiv zoo yog txuam nrog kev hloov pauv uas muaj txiaj ntsig zoo rau tus kab mob uas lawv tshwm sim. SARS-CoV-2 tau ua pov thawj tias yog tib neeg cov kab mob muaj peev xwm ua tau zoo, tab sis kuj yog ib tus kws tshaj lij ntawm cov tswv cuab tropism, tsim cov kab mob hauv ntau hom tsiaj txhu, suav nrog kev kis kab mob hauv cov mink4 ua liaj ua teb, qhov chaw ruaj khov hauv cov kab dawb-tailed. mos lwj 5,6 thiab kis kab mob ntawm ntau lwm yam tsiaj 7. Thaum SARS-CoV-2 nyob rau hauv tib neeg, thawj lub hlis ntawm SARS-CoV-2 evolution yog tus cwj pwm los ntawm kev hloov pauv tsis pub dhau thiab kev hloov pauv phenotypic cuam tshuam rau nws cov evolution tom qab8. Thawj qhov kev hloov pauv tseem ceeb, ib qho kev hloov pauv loj heev (D614G), tau tshwm sim thaum ntxov ntawm kev kis tus kabmob kis thoob ntiaj teb thiab tau pom zoo txog kev loj hlob ntawm 20% piv rau qhov sib txawv ua ntej 9. Ib kab lus uas txhais los ntawm D614G (PANGO lineage10 B.1) sai sai tau los ua tus tseem ceeb hauv Tebchaws Europe, muab qhov qhia ntxov ntawm lub peev xwm rau SARS-CoV-2 kom nce nws kis tau rau tib neeg. Raws li peb tau piav yav dhau los 3,11, txij lub Kaum Hli 2020 mus ntxiv, tshiab, ntau qhov hloov pauv ntau ntawm SARS-CoV-2 variants pib tshwm sim. Cov kev hloov pauv no tau txawv los ntawm cov lej ntau dua ntawm cov kev hloov pauv uas tsis yog qhov sib txawv ntawm qhov tseem ceeb hauv cov protein ntau - tshwj xeeb yog rooj plaub rau Omicron - thiab cov khoom sib txawv phenotypic, suav nrog kev hloov pauv hloov pauv thiab antigenicity. Txog niaj hnub no, tsib tus kab mob SARS-CoV-2 tau tshaj tawm qhov txawv ntawm kev txhawj xeeb (VOCs) los ntawm World Health Organization (thiab cov koom haum saib xyuas kev noj qab haus huv hauv tebchaws) vim tias lawv pom muaj kev hloov pauv hloov pauv ntau lossis tiv thaiv kev tiv thaiv, ceeb toom rau kev saib xyuas ze. . Txhua VOC tau qhia txog qhov zoo ntawm kev sib kis dhau los thiab tau dhau los ua qhov tseem ceeb, hauv cheeb tsam hauv cov xwm txheej ntawm Alpha (PANGO lineage10 B.1.1.7), Beta (B.1.351), thiab Gamma (P.1) - hauv Tebchaws Europe, yav qab teb Africa, thiab South America, ntsig txog - lossis thoob ntiaj teb, hauv cov xwm txheej ntawm Delta (B.1.617.2 / AY sublineages) thiab ntau Omicron sublineages (B.1.1.529 / BA sublineages, xws li BA.1, BA.2 thiab BA .5).
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Nyob rau hauv qhov sib piv rau qhov kev cia siab tias cov kab mob tau txais kev hloov pauv sai sai tom qab spillover12,13, kev tshuaj xyuas kev xaiv qhia tau hais tias SARS-CoV-2 tsis muaj qhov tseem ceeb ntawm kev saib xyuas kev hloov pauv thaum ntxov ntawm kev sib kis 14. Tom qab ntawd nws tau pom tseeb tias SARS-CoV-2 yog tus kab mob dav dav uas muaj peev xwm siv ntau hom tsiaj txhu angiotensin-hloov enzyme 2 (ACE2) membrane proteins rau cell entry15, ua kom muaj kab mob ntau yam ntawm cov tsiaj txhu 14,16. Cov kab mob sarbecoviruses kis tau ntau zaus ntawm cov kab sib txawv horseshoe bat species17 thiab non-bat hom nrog ACE2-binding peev xwm (tus poj koob yawm txwv zoo nyob rau hauv sarbecoviruses18), uas tshwm sim suav nrog tib neeg. SARS CoV-2 spike protein muaj cov khoom tseem ceeb uas muaj lub luag haujlwm thiab xav tau rau kev sib kis ntawm tib neeg mus rau tib neeg, tshwj xeeb: human ACE2 binding thiab polybasic furin cleavage site (FCS) ntawm S1-S2 junction19,20 . Tam sim no SARS-CoV-2 S1–S2 FCS yog qhov tshwj xeeb ntawm cov kab mob arboviruses, txawm hais tias muaj kev sib piv ntawm lwm cov betacoronaviruses. Kev nkag mus ntawm SARS-CoV-2 mus rau hauv cov hlab ntsws yuav tsum tau furin-mediated cleavage ntawm FCS, ua kom cov membrane fusion. FCS yog li ntawd yog ib qho kev txiav txim siab tseem ceeb ntawm kev kis tus kab mob siab ntawm SARS-CoV-2, ua rau nws muaj txiaj ntsig zoo rau tib neeg. Kev ua kom zoo ntxiv ntawm cov tsiaj qus FCS thaum lub sijhawm muaj kev sib kis tau ua rau muaj kev txhim kho furin cleavage ntawm Alpha thiab Delta spike proteins22–25. Hauv kev hais kwv txhiaj nrog lwm yam kev hloov pauv, tshwj xeeb tshaj yog cov kev txhim kho ACE2 binding26,27, kev hloov pauv ua kom zoo dua furin cleavage tau xav tias tau pab txhawb kev sib kis tau zoo, thiab yog li kev noj qab haus huv, ntawm Alpha thiab Delta VOCs, nrog 65% thiab 55% siab dua cov txheeb ze sib kis piv nrog variants lawv hloov, feem 28-30. Nyob rau hauv sib piv rau Alpha thiab Delta, evolutionary kev vam meej ntawm lub Omicron variant tsis txuas mus rau optimization ntawm furin cleavage. Hloov chaw, Omicron yog tus cwj pwm los ntawm kev hloov pauv nkag phenotype31,32, ua ke nrog kev tiv thaiv kab mob tseem ceeb 31,33,34, ua kom muaj txiaj ntsig zoo ntawm kev txhaj tshuaj tiv thaiv lossis yav dhau los cov neeg mob. Txawm hais tias kev kis tus kab mob hauv cov neeg tsis paub lus yog feem ntau txiav txim siab los ntawm cov kab mob hauv nruab nrog cev, qhov chaw tiv thaiv kab mob nce zuj zus nyob rau hauv uas SARS-CoV-2 tam sim no kis tau txhais tau tias cov tshuaj tiv thaiv kev khiav tawm (raws li kev sib kis tau raug txhim kho los ntawm tus kab mob biology ib leeg, ib qho zoo li. Tej zaum yuav nyuaj rau kev ua kom zoo dua li qhov ua tiav los ntawm Omicron) tau dhau los ua tus tsav tsheb tseem ceeb ntawm kev ua tau zoo sib txawv. Ua ntej Omicron qhov tshwm sim (Lub thawv 1), txhua qhov sib txawv tseem ceeb tau hloov zuj zus los ntawm cov neeg ua ntej VOC, tsis yog hloov los ntawm ib leeg. Los ntawm qhov sib txawv, tam sim no cov nthwv dej txuas ntxiv tau tshwm sim los ntawm Omicron sublineages (piv txwv li, BA.5, ib qho ntawm nws cov sublineages BQ.1, thiab BA.2.75, sublineage ntawm BA.2). Ntawm qhov kev ceeb toom, nws muaj peev xwm hais tias qhov kev hloov pauv tsis tau tshawb pom, muaj peev xwm ua kom rov ua dua tshiab (Box 2), tuaj yeem tshwm sim nrog kev sib kis tau zoo txuas mus rau cov khoom siv hauv nruab nrog cev thiab cov khoom tshiab antigenic. Txawm hais tias tus kab mob tshiab tshwm sim tag nrho, lossis cov kab mob yav tom ntej hloov zuj zus los ntawm Omicron sublineages nrog cov kev hloov pauv tshiab antigenic (ntau tuaj yeem tshwm sim raws li VOCs yav dhau los tsis tau nthuav tawm), nws yog qhov tseeb tias cov tshiab SARS-CoV-2 variants muaj qhov sib txawv ntawm kev hloov pauv. yuav tshwm sim txuas ntxiv thiab cov uas muaj lub zog kom zoo dua yuav ua tus txheeb ze rau yav dhau los variants. Txog niaj hnub no, cov kev hloov pauv tau zoo kuj tau nthuav tawm cov kev hloov pauv hauv cov xwm txheej hauv chaw kho mob, suav nrog kev mob hnyav, kev tiv thaiv kev tiv thaiv, thiab kev nkag siab zoo rau kev kho mob (tshwj xeeb yog monoclonal antibodies). Yog li ntawd nws yog qhov tseem ceeb ntawm kev noj qab haus huv rau pej xeem thiab kev kho mob tseem ceeb kom nkag siab txog tus neeg tsav tsheb ntawm SARS-CoV-2 kev nyab xeeb. Kev tawm dag zog sib txawv - tus kab mob kev ua tiav ntawm kev yug me nyuam - nyob ntawm ntau yam uas txiav txim siab nws lub peev xwm kis tau, rov ua dua, thiab sib kis ntawm cov tswv. Hauv Kev Ntsuam Xyuas no, peb muab cov ntsiab lus ntawm cov kev hloov pauv uas tau piav qhia tias cuam tshuam rau SARS-CoV-2 kev kis kab mob thiab kis tau zoo thiab sib tham txog qhov muaj peev xwm kis tau los ntawm T cell-mediated, innate, lossis humoral immunity11. Saib peb qhov kev tshuaj xyuas yav dhau los11 kom paub meej ntxiv txog kev tiv thaiv kab mob sib kis.
Antigenic escape and SARS-CoV-2 variants
Ib qho kev txhawj xeeb ntxov txog SARS-CoV-2 evolution yog qhov muaj peev xwm tshwm sim ntawm cov tshuaj tiv thaiv kab mob sib txawv nrog lub peev xwm los tiv thaiv cov tshuaj tiv thaiv- lossis kev tiv thaiv kab mob kis tau, raws li ua piv txwv los ntawm N439K spike hloov pauv35. Ua ntej lawv hloov tshiab thaum xyoo 2022, txhua qhov kev siv dav dav rau COVID-19 cov tshuaj tiv thaiv tau ua raws li cov tshuaj tiv thaiv kab mob sib kis ntawm cov kab sib txawv thaum ntxov, feem ntau siv cov kab lus siv Wuhan-Hu-1, piv txwv los ntawm kab mob B ntawm Huanan Kev lag luam nqaij nruab deg, feem ntau muaj kev hloov pauv uas ruaj khov cov protein ntau nyob rau hauv ib qho kev sib koom ua ke36. Txawm hais tias muaj qee qhov kev hloov pauv antigenic tau tshaj tawm rau Alpha25,37,38, kev khiav tawm nruab nrab ntawm cov tshuaj tiv thaiv tau los ntawm cov tshuaj tiv thaiv kab mob thiab convalescent sera tau pom rau Beta, Gamma, thiab Delta hauv kev sim 23,37-39. Txawm li cas los xij, kev tshawb fawb txog kab mob kis tau muab pov thawj tias cov tshuaj tiv thaiv zoo tiv thaiv Delta thiab Beta tau khaws cia ntau 40-42. Yog li, txawm tias muaj kev tsim qauv raws li qhov tshwm sim ntxov heev, thawj tiam SARS CoV-2 cov tshuaj tiv thaiv tau muab kev tiv thaiv zoo kawg nkaus tiv thaiv kab mob hnyav thiab ua rau ntau lub ntiaj teb rov qab los rau qhov zoo li qub.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
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Lub thawv 1
Keeb kwm ntawm SARS-CoV-2 variants of concern and the Omicron complex
Mob hnyav ua pa nyuaj siab mob coronavirus 2 (SARS-CoV-2) variants ntawm kev txhawj xeeb (VOCs) nthuav tawm ntau yam khoom sib txawv, ib qho ntawm qhov txaus nyiam tshaj plaws yog qhov ntev phylogenetic ceg ntev feem ntau nrog tsis muaj genetic intermediates ua ntej lawv. nrhiav pom 67,193,194. Alpha tau kuaj pom thawj zaug hauv tebchaws Askiv thaum lub sijhawm muaj tus kabmob kis qis thiab tsis tau pom dua SARS-CoV-2 soj ntsuam67,131. Delta tau pom thawj zaug hauv Is Nrias teb thaum Lub Plaub Hlis 2021 (ref. 195) thiab tom qab ntawd tau cuam tshuam nrog kev sib kis tshiab nthwv dej hauv UK196, tsim ntau qhov sublineages, qee qhov kis tau ntau dua li niam txiv Delta, piv txwv li, AY.4.2 (ref. . 197). Ib yam li ntawd, Omicron complex ntawm variants muaj cov ceg ntev ntev thiab kev hloov pauv ntau dua li VOCs43,44 ua ntej. Qhov tsis muaj qhov sib txawv nruab nrab tau ua rau ntau qhov kev xav ntawm VOC lub hauv paus chiv keeb198: (1) kev ncig hauv thaj chaw tsis muaj qauv; (2) cryptic ncig nyob rau hauv ib tug tsiaj reservoir tom qab rov qab zoonosis ntawm ib tug thaum ntxov variant; (3) evolution nyob rau hauv ib tug mob ntev nyob rau hauv ib tug tiv thaiv kab mob los yog ntau tus tib neeg hosts. Txawm hais tias muaj pov thawj rau kev tsim cov tsiaj txhu ruaj khov rau SARS-CoV-2, tshwj xeeb tshaj yog nyob rau hauv cov mink ua liaj ua teb thiab cov mos lwj dawb-tailed4,5,186, tam sim no qhov 'mob kab mob hypothesis' ntawm variant tshwm sim yog qhov zoo tshaj plaws txhawb nqa ntawm cov no. xwm 67,183. Cov kab mob sib kis tau paub tias yuav tsav cov kev hloov pauv uas zoo ib yam li VOCs113,184,199–201. Kuj tseem muaj pov thawj rau kev txwv tsis pub kis tus kab mob mus ntev ua rau muaj kev sib kis hauv zos 113,182. Kev hloov mus sij hawm ntev hauv qhov muaj qhov tsis tu ncua ntawm cov tshuaj tiv thaiv kab mob tsis tu ncua tuaj yeem piav qhia VOC antigenic nrug, tshwj xeeb tshaj yog rau Omicron. Tsis zoo li lwm cov VOCs, Omicron tau hloov pauv ntau yam zoo kawg nkaus ua ntej raug kuaj pom thawj zaug thiab tam sim no tau muab faib ua tsib kab loj (BA.1, BA.2, BA.3, BA.4, thiab BA.5 (ref. 43); saib cov daim duab), nrog ntau ntau sublineages raug kuaj pom uas yog accumulating ntxiv antigenic hloov157. BA.1 ua rau muaj kev kis kab mob thoob ntiaj teb thaum kawg ntawm 2021, tab sis thaum ntxov 2022, nws tau hloov los ntawm BA.2. Lub Plaub Hlis 2022, ntxiv BA sublineages, BA.4 thiab BA.5, tau lees paub, thiab, txij li lub Cuaj Hlis 2022, BA.5 tau tsav lub Omicron nthwv dej tshiab thoob ntiaj teb43. Cov kab mob Omicron qhia txog kev sib raug zoo rau ib leeg, uas yuav suav nrog ntau qhov kev sib koom ua ke ntawm VOC ua ntej kuaj pom 43,44. Piv txwv li, BA.4 thiab BA.5 muaj ze li 5' qhov kawg ntawm genome mus txog rau M gene, tab sis qhia qhov sib txawv loj tom qab qhov no, qhia txog qhov kev tshwm sim tsis ntev los no. Ib yam li ntawd, BA.3 tuaj yeem pom tau tias yog qhov sib xyaw ua ke ntawm cov poj koob yawm txwv BA.1 thiab BA.2 viruses44. Hypothetical phylogenetic keeb kwm ntawm Omicron complex uas qhia ib lub peev xwm ntawm recombination ntawm sublineages BA.1, BA.2, BA.3, BA.4, thiab BA.5 yog qhia nyob rau hauv daim duab. Cov npe ntawm cov protein qhia txog kwv yees (~) qhov muaj peev xwm tawg.
Omicron 'complex' - suav nrog cov sublineages sib txawv BA.1, BA.2, BA.3, BA.4, thiab BA.5 (Box 1) - muaj peev xwm kis tau cov tshuaj tiv thaiv thiab yav dhau los kis, ua rau muaj kev sib tw ntawm Kev xaiv cov tshuaj tiv thaiv kab ke thiab cov tshuaj tiv thaiv thoob ntiaj teb rau ua ntej ntawm SARS-CoV-2 kev sib tham txog kev tswj hwm. Nrog ntau tshaj 15 spike receptor-binding domain (RBD) kev hloov pauv thiab ntau cov tshuaj tiv thaiv kev tshem tawm thiab hloov pauv hauv cov amino-terminal domain (NTD) 43,44, BA.1, BA.2, BA.4 thiab BA.5 yog ua tsis tau zoo heev nrog cov tshuaj tiv thaiv thawj tiam thiab los ntawm cov tshuaj tiv thaiv kab mob ua ntej Omicron (Daim duab 1). Tsis tas li ntawd, kev khiav tawm ntawm feem ntau ntawm cov tshuaj kho monoclonal antibodies tam sim no tau tshwm sim; tam sim no, tsuas yog bebtelovimab - ib qho tshuaj tiv thaiv kab mob monoclonal tsom rau RBD ntawm cov protein ntau - tau tshaj tawm kom khaws nws cov txiaj ntsig tiv thaiv tag nrho SARS-CoV-2 variants31,33,34,38,45–50. Qhov loj antigenic 'hloov' no tau ua rau qee tus tswv yim hais tias Omicron cov kab mob yuav tsum raug suav hais tias yog ib hom kab mob sib cais lossis serotype piv nrog cov kab mob ua ntej Omicron51,52. Qhov tseem ceeb, qhov loj ntawm qhov kev hloov pauv antigenic no tau cuam tshuam los ntawm cov ntaub ntawv ntawm cov tshuaj tiv thaiv hauv ntiaj teb tiag tiag tiv thaiv kab mob thiab cov tsos mob 41,53-57. Cov koob tshuaj Booster yuav tsum tau tswj hwm cov tshuaj tiv thaiv zoo tiv thaiv Omicron, uas txo qis raws li cov tshuaj tiv thaiv kab mob titers wane41,55. Tseeb tiag, kev txhaj tshuaj tiv thaiv kab mob hnyav rau Omicron tseem nyob siab 4 lub hlis tom qab txhaj tshuaj tiv thaiv kab mob thiab tom qab ntawd txo qis sai, txawm hais tias qhov txo qis dua sai dua qhov pom tom qab txhaj tshuaj tiv thaiv thawj zaug58. Vim lub sijhawm luv luv ntawm kev tiv thaiv kab mob Omicron nrog cov tshuaj tiv thaiv tam sim no, ntau lub tuam txhab tshuaj tiv thaiv thiab kev kawm tau tsom mus rau cov tshuaj tiv thaiv thib ob, xws li monovalent lossis bivalent Omicron-specific boosters59 (uas tab tom siv tam sim no), tshuaj tiv thaiv qhov ntswg xa mus rau txhawb kev tiv thaiv mucosal ntau dua 60 lossis universal vaccine approaches61. Ib yam nrog rau tib neeg tus mob coronaviruses raws caij nyoog, qhov ntev npaum li cas ntawm kev tiv thaiv kab mob tuaj yeem tiv thaiv kev rov qab los ntawm SARS-CoV-2 raug txwv vim muaj kev sib xyaw ntawm cov tshuaj tiv thaiv kab mob waning thiab tus kab mob antigenic drift - qhov nce ntxiv ntawm kev hloov pauv uas tso cai rau kev tiv thaiv kab mob. kev 62,63. Ntxiv rau cov kauj ruam hloov pauv hauv kev tiv thaiv kab mob, kev hloov pauv tus kab mob thaum muaj kab mob tsis tu ncua tau ua rau SARS-CoV-2 txhawm rau khaws ntau yam kev hloov pauv hauv cov ntsiab lus ntawm ib qho lossis ob peb tus kab mob mus ntev, ua rau muaj kev hloov pauv hloov pauv hauv cov xwm txheej thaum cov kev hloov pauv no mus. mus kis rau lwm tus (Ntev 1).
Lub thawv 2
SARS-CoV-2 recombinants
Thaum ob tus kab mob RNA sib koom ua ke ntawm tib lub xov tooj hauv ib tus neeg, muaj lub caij nyoog siab thaum lub sij hawm genome replication uas cov polymerase yuav hloov los ntawm ib tug genome sequence template mus rau heterologous genome. Qhov no ua rau muaj tus kab mob recombinant nrog ib feem ntawm nws cov genome los ntawm ib tug 'niam txiv' thiab cov genomic seem ntawm lwm tus (saib daim duab, ntu a). Ntau cov kab mob sib txuas tau raug txheeb xyuas nyob rau hauv qhov chaw sib txawv thiab raug xaiv los ntawm PANGO kev faib tawm txij li xyoo 2020 (ref. 10), txheeb xyuas los ntawm 'X-' kab lus ua ntej. Recombinants tau raug txheeb xyuas tsis meej thaum cov kab mob sib txawv, xws li ob qho kev txhawj xeeb, muaj kev sib koom ua ke ua rau muaj kev sib kis. Piv txwv li, thawj cov kab mob sib txuas ua ke, XA, yog ib qho kev sib txuas ntawm Alpha (B.1.1.7) thiab cov kab mob yav dhau los nyob hauv UK, B.1.177 (ref. 202). XC yog recombinant ntawm Alpha thiab Delta pom nyob rau hauv Nyiv203. Txij li thaum pib ntawm 2022, tus naj npawb ntawm cov recombinants txheeb xyuas tau nce sai, uas yuav yog vim muaj kev sib koom ua ke ntawm Delta thiab BA.1, lossis BA.1 thiab BA.2, hauv ntau lub tebchaws thaum lub sijhawm ua haujlwm tawm. ntawm COVID-19 txwv. Lwm qhov kev piav qhia yog kev ntseeg siab zoo dua hauv kev txheeb xyuas cov recombinants, vim muaj qhov sib txawv ntau dua ntawm cov genomes ntawm Delta, BA.1, thiab BA.2. Ib qho piv txwv recombinant yog XD - Delta × BA.1 recombinant thawj zaug pom nyob rau lub Ib Hlis 2022 hauv France204. XD muaj ob lub genome breakpoints, nrog ib tug txha nraub qaum thiab ib feem ntawm qhov spike protein amino-terminal domain los ntawm Delta thiab cov seem ntawm cov protein spike los ntawm BA.1 (saib daim duab, ntu b). Functionally, XD tau pom tias muaj qhov nruab nrab pathogenicity phenotype ntawm BA.1 thiab Delta hauv cov nas transgenic qhia txog tib neeg angiotensin-hloov enzyme 2 (ACE2) raws li kev tswj hwm ntawm keratin 18 txhawb nqa, ua rau poob qis, qhia txog ib feem ntawm qhov sib txawv. Nav pathogenicity phenotype ntawm Delta thiab BA.1 daim ntawv qhia sab nraum lub pob txha protein204. Qhov thib ob tseem ceeb recombinant hauv UK yog BA.1 × BA.2 recombinant XE, uas tau pom thawj zaug hauv tebchaws Askiv thaum Lub Ib Hlis 19, 2022. Ua ntej nws tau tshaj tawm los ntawm BA.5, XE muaj ntau dua 2,500 genomes, feem ntau yog los ntawm UK. , thiab cov ntaub ntawv ua ntej qhia txog kev loj hlob me me piv nrog BA.2 (ref. 205).
FCS in SARS-CoV-2 variant emergence
Piv nrog rau lwm cov kab mob arboviruses paub, qhov tshwj xeeb ntawm SARS CoV-2 yog qhov muaj FCS nyob rau hauv nws cov kab mob sib kis uas tuaj yeem cleaved los ntawm furin. FCSs tseem muaj nyob hauv ntau lwm beta coronaviruses ntawm subgenera Embecovirus thiab Merbecovirus, xws li tib neeg tus mob coronavirus OC43, human coronavirus HKU1, thiab Middle East respiratory syndrome coronavirus (Fig. 2a). SARS-CoV-2 FCS tau pom tias yog qhov tseem ceeb rau kev pom cov kab mob zoo tshaj plaws nyob rau hauv tib neeg txoj hlab ntsws hlwb64, transmissibility19,21 thiab pathogenicity65. Furin, tus tswv tsev protease, muaj ntau tshaj plaws nyob rau hauv Golgi apparatus, tso cai rau cleavage thaum lub sij hawm kev lag luam ntawm tus kab mob mus rau lub cell nto66. Tam sim no nws yog qhov tseeb, txawm li cas los xij, FCS ntawm SARS-CoV thaum ntxov-2 variants yog qhov zoo tshaj plaws thiab tsis muaj txiaj ntsig zoo los ntawm furin19,24,65. Interestingly, ib qho ntawm cov luag hauj lwm tau piav qhia txog kev hloov pauv thaum ntxov, spike D614G, tau ua kom zoo dua qub (saib xyuas hauv kev nthuav dav yav dhau los). Ntau tus tom qab SARS-CoV-2 variants harbor mutations uas nyob ib sab ntawm FCS, uas ua rau muaj cov amino acid residues - qhov chaw paub txog furin; Piv txwv li, Alpha, Mu, thiab Omicron muaj FCS kev hloov pauv P681H44,67,68, uas tau kwv yees tias yuav ua rau muaj kev cuam tshuam ntau ntxiv. Ntxiv mus, qhov kev hloov pauv sib txawv ntawm tib txoj haujlwm, P681R, txhim kho qhov kev rov ua dua thiab cov kab mob ntawm Delta VOC23,30,69 (Fig. 2b). Ntawm qhov kev ceeb toom, Omicron muaj P681H, nrog rau kev hloov pauv ntxiv N679K44, uas ua ke ua rau muaj qhov ua tau zoo FCS19,23–25,32,70. Qhov tseem ceeb, txawm li cas los xij, furin site optimization ib leeg tsis txhim kho kev sib kis lossis rov ua dua ntawm SARS-CoV-2 thiab tej zaum yuav ua rau muaj kev cuam tshuam rau kev kis tus kab mob 27, qhia tias kev hloov pauv ntxiv pom hauv cov kev hloov pauv no yuav tsum tau ua kom zoo dua qub thiab kis tau zoo. Qhov tseeb mechanism uas tau pom FCS kev hloov pauv txhim kho furin cleavage tseem yog lub ntsiab lus ntawm kev sib cav. Txawm hais tias muaj pov thawj muaj zog heev uas P681R ncaj qha txhim kho furin kev koom tes thiab kev sib cais ntawm S1-S2 site19,24,69, qhov ua tau zoo ntawm P681H71 tsis meej. Mechanistically, nws yuav muaj feem cuam tshuam rau txoj haujlwm T678 ntawm cov protein ntau, nyob ze rau qhov seem P681, tuaj yeem hloov kho tom qab hloov pauv nrog O-txuas glycosylation site-74. Downstream prolines paub los txhawb O-txuas glycosylation; Yog li ntawd, lwm txoj kev piav qhia yuav yog qhov kev tshem tawm ntawm P681, es tsis yog qhov sib ntxiv ntawm histidine ib se, ua rau poob ntawm qhov muaj peev xwm furin-obstructing glycosylation site thiab cuam tshuam kev txhim kho ntawm cleavage. Kev nkag siab tsis ntev los no rau Omicron biology tau tawm tsam qhov kev xav tias kev txhim kho kev sib kis kab mob yog qhov tseem ceeb rau kev kis tus kab mob ntau ntxiv. Tag nrho cov kab mob Omicron muaj P681H thiab N679K43,44, uas ib leeg, lossis ua ke, txhim kho qhov sib cais ntawm qhov chaw S1-S2 hauv cov tsiaj qus-hom spike protein 32,70. Txawm li cas los xij, nyob rau hauv cov ntsiab lus ntawm tag nrho Omicron spike protein, pov thawj ntawm qhov kev txhim kho cleavage yog tsawg dua, nrog rau qee cov kev tshawb fawb pom tias S1-S2 hlws ris zoo nkaus li tsis zoo cleaved dua nyob rau hauv yav dhau los VOCs50,75, whereas lwm tus qhia cleavage efficiency piv rau qhov ntawd. ntawm Delta32,76,77. Txawm hais tias cleavage phenotype, ntau pab pawg tau piav qhia tias Omicron muaj peev xwm siv tau lwm txoj hauv kev nkag ntawm tes. Qhov tseeb, thaum yav dhau los VOCs xws li Delta muaj kev vam khom rau fusion priming los ntawm transmembrane protease serine 2 (TMPRSS2) ntawm lub xov tooj ntawm tes, Omicron kuj tseem tuaj yeem ua tau zoo los ntawm endosomal proteases, xws li cathepsins, zoo ib yam li SARS- CoV 31,32,50,75,76,78,79. Qhov kev hloov pauv no yog xav tias yog ib feem ntawm lub luag haujlwm rau qhov txo qis ntawm Omicron, tsawg kawg hauv cov nas qauv 32,75,78,80,81, vim qis fusogenicity thiab muaj peev xwm hloov cov ntaub so ntswg tropism, nrog rau kev tsis ncaj ncees rau kev kis tus kab mob sab sauv. tshaj qhov ua pa sab hauv. Ntau qhov kev tshawb fawb tau qhia txog cov txheej txheem molecular rau qhov txo qis fusogenicity thiab hloov pauv txoj hauv kev, suav nrog kev hloov pauv hauv qhov loj RBD ntawm Omicron31,82, H655Y83 lossis kev hloov pauv hauv S2 domain31,32,76, tshwj xeeb N969K32, txawm hais tias nws muaj kev sib cav txawm tias qhov zoo li no tau khaws cia. nyob rau tag nrho Omicron kab 32,84. Txawm li cas los xij, Omicron cov kab mob txuas ntxiv ua kom pom kev sib kis tau zoo, tsawg kawg yog sib npaug ntawm Delta85, 86, txhais tau tias muaj peev xwm decoupling ntawm qhov ua tau zoo ntawm furin cleavage thiab fusogenicity thiab lawv cov kev koom tes rau kev kis tus kab mob. Dhau ntawm qhov chaw S1-S2, betacoronaviruses tseem xav tau kev sib cais ntawm qhov thib ob protease cleavage site, hu ua S2' site. Tom qab cleavage ntawm S1-S2 qhov chaw thiab cognate receptor binding, S2' site yuav tshwm sim nyob rau hauv S2 domain ntawm spike protein87. Cleavage ntawm S2' ncaj qha tso tawm fusion peptide, ua rau tus kab mob-tus tswv tsev membrane fusion88-90. Rau SARS-CoV-2 nkag mus rau hauv cov hlab ntsha hauv cov hlab ntsha, qhov chaw no yog qhov tshwj xeeb tshaj tawm los ntawm tus tswv serine proteases, xws li TMPRSS2, tab sis nws tuaj yeem hloov pauv los ntawm endolyosomal cathepsins19,91. Ib tug xov tooj ntawm cov kab lus tsis ntev los no tau qhia tias kev hloov pauv hauv NTD ntawm SARS-CoV{117}}, tshwj xeeb tshaj yog los ntawm kev hloov kho cov voj voog sab nraud los ntawm kev nrhiav tau ntawm kev tshem tawm lossis kev ntxig, tuaj yeem cuam tshuam rau S1-S2 cleavage thiab S2′ cleavage, thiab yog li ntawd fusion92–94. Zuag qhia tag nrho, kev sib raug zoo ntawm kev siv protease, S1-S2 cleavage efficiency, tropism, pathogenicity, thiab transmissibility ntawm SARS CoV-2 yog qhov nyuaj heev, thiab, qee zaum, cov txiaj ntsig ntawm cov kev tshawb fawb tau tsis sib haum. Kev ua haujlwm ntxiv yog, yog li, yuav tsum tau txuas cov qhov khoob hauv kev paub thiab kom nkag siab tag nrho cov txheej txheem no.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Lwm cov txheej txheem thiab cov txheej txheem tsis yog cov protein thiab cov kab mob
Ntau qhov kev tshawb fawb tsis ntev los no tau tshawb xyuas qhov tshwm sim ntawm kev hloov pauv hauv cov txheej txheem cov protein uas tsis yog cov protein ntau, suav nrog daim nyias nyias (M), lub hnab ntawv (E), thiab nucleocapsid (N) cov proteins. Cov kab mob B.1.1 yog txhais los ntawm ob qho kev hloov pauv hauv N protein - R203K thiab G204R. Variants muab tau los ntawm B.1.1 (xws li Alpha, Gamma, thiab Omicron) tau txais kev hloov pauv tib yam, thaum Delta thiab Beta ntawm nws tus kheej hloov pauv R203M thiab T205I, raws li, nrog rau cov khoom siv sib xyaw ua ke. Tshwj xeeb, cov kev hloov pauv no tau pom tias ua rau muaj kab mob sib kis ntau dua 95-97, txawm hais tias qhov tseeb ntawm kev ua haujlwm tseem tsis sib cav. Ntawm ib sab, cov ntaub ntawv los ntawm tus kab mob zoo li tus kab mob raws li tus neeg sau xov xwm-raws li assay95 qhia tias cov kev hloov pauv ncaj qha nce tus kab mob particle tsim, hos lwm daim ntawv tshaj tawm qhia txog lub luag haujlwm rau phosphorylation ntawm N protein uas tso cai rau kev khiav tawm los ntawm kinase GSK3 (ref. 97. ). Lwm qhov kev piav qhia yog tias qhov kev hloov pauv R203K thiab G204R qhia txog qhov chaw hloov pauv hloov tshiab rau hauv nruab nrab ntawm N gene, tso cai rau kev nthuav tawm ntawm daim ntawv luv luv ntawm N protein (lub npe 'N *' lossis 'N.iORF3'), uas tej zaum yuav txhim kho tus kab mob kis los ntawm kev txhim kho interferon antagonism98,99. Interestingly, muaj ob peb ntxiv piv txwv ntawm SARS-CoV-2 kab evolving tshiab transcriptional regulation site sequences uas yuav ua tau nyob rau hauv cov kev qhia ntawm truncated protein cov khoom, txawm nyob rau hauv thav duab los yog tawm ntawm lub thav duab, feem ntau pronounced nyob rau hauv non-structural protein 16. (NPO 16) 98.
Nrog rau N protein, kev hloov pauv hauv M thiab E cov proteins kuj tau cuam tshuam rau hauv kev hloov kho SARS-CoV-2 kis kab mob. Kev hloov pauv hauv M thiab E cov proteins ntawm BA.1 (Omicron) tau pom tias txo qis kev nkag ntawm cell ntawm cov kab mob zoo li cov kab mob, txawm hais tias cov kev hloov pauv no tau them nyiaj los ntawm kev hloov pauv ntxiv hauv S thiab N proteins100. Coronavirus E cov proteins muaj ntau lub luag haujlwm, ib qho yog ua raws li cation channel, muaj peev xwm nyob rau hauv endoplasmic reticulum (ER) thiab Golgi compartments los tswj ntau theem ntawm kab mob lub neej 101. Kev hloov pauv T9I pom nyob rau hauv Omicron E protein tau pom tias txo qis qhov kev ua haujlwm ion channel hauv vitro102, txawm hais tias nws cov txiaj ntsig ua haujlwm tsis meej. Txawm hais tias ORF1ab ua rau ob feem peb ntawm SARS-CoV-2 genome, nws tseem yog thaj av uas qhov cuam tshuam ntawm kev hloov pauv tsis tshua nkag siab. Ib qho kev zam yog kev tshem tawm ntawm txoj haujlwm 106-108 hauv NSP6, kev hloov pauv uas tau khaws cia ntawm tag nrho VOCs tshwj tsis yog Delta. NSP6 yog multipass transmembrane protein uas cuam tshuam nrog kev tsim cov kab mob coronavirus replication organelle - ER-los ntawm membranous qauv uas yog tsim thaum kis kab mob, muab ib tug compartment rau tus kab mob RNA replication shielded los ntawm innate immunity103. Ib txoj kev tshawb fawb tsis ntev los no tau pom tias NSP6 tsim homodimers thiab kho qhov tsim ntawm 'zippered ER' - nqaim thiab tshwj xeeb membranous raws uas txuas 'ob chav membrane vesicles', uas yog thawj qhov chaw ntawm viral genome replication103. Nws tau pom tias 106-108 kev tshem tawm hauv NSP6 tshwj xeeb txhim kho kev tsim ntawm qhov zippered ER, qhia txog qhov muaj peev xwm hloov kho tus tswv tsev tshwj xeeb. Cov txheej txheem tseeb ntawm qhov kev txhim kho no tseem yuav tsum tau piav qhia, txawm hais tias cov kws sau ntawv tshawb fawb tau tshaj tawm tias qhov kev tshem tawm tshem tawm qhov chaw tso O-txuas glycosylation. Tam sim no nws tseem tsis tau paub meej tias vim li cas Delta thiab ntau qhov sib txawv tsis tau pom tias tau txais qhov kev hloov pauv no txawm tias qhov yooj yim uas qhov kev tshem tawm no tuaj yeem tshwm sim. Tshaj li cov qauv tsim thiab ORF1ab cov proteins, muaj qee cov pov thawj tsawg heev uas qhia txog kev hloov pauv hauv cov khoom siv protein, uas tau hais hauv qab no hauv Kev Ntsuam Xyuas. Hmoov tsis zoo, kev sim ua tus cwj pwm ntawm cov kev hloov pauv tsis sib xws thiab cov kev hloov pauv cuam tshuam rau tib neeg hauv SARS-CoV-2 variants tseem nyob deb ntawm cov protein ntau. Qhov no yog vim muaj ntau yam, suav nrog kev siv ubiquitousness ntawm pseudovirus technology siv los kawm spike phenotypes piv nrog cov kev nyuaj ntawm cov noob caj noob ces rov qab (feem ntau yuav tsum tau rau kev tshawb fawb txog kab mob ntawm cov kab mob tsis sib xws) thiab qhov tsis txaus ntawm cov kab mob hauv vitro rau kev tshawb nrhiav tsis. - cov protein ntau. Nws yog qhov tseeb los ntawm kev ua haujlwm tam sim no tias kev hloov pauv tsis zoo ua rau muaj txiaj ntsig zoo rau tus kab mob thiab kab mob, thiab kev txhim kho txuas ntxiv ntawm cov kab ke los kawm cov cheeb tsam no yog qhov tseem ceeb rau kev tshawb fawb tsis tu ncua.
T-cell teb thiab antigenic khiav
T hlwb yog ib feem tseem ceeb ntawm kev hloov lub cev tiv thaiv kab mob rau SARS-CoV-2 tus kab mob, nrog rau CD4+ T cell thiab CD8+ T cell teb pom nyob rau hauv feem ntau cov neeg mob104. Ntau qhov kev tshawb fawb qhia txog lub luag haujlwm tseem ceeb rau T cell tiv thaiv kev tiv thaiv los ntawm COVID hnyav-19, txawm hais tias qhov no yuav muaj ntau dua nuanced thiab complex dua li cov yam ntxwv zoo sib xws ntawm kev tiv thaiv los ntawm kev kis tus kab mob neutralizing antibody teb105,106. Txawm hais tias CD4+ pab T cell cov lus teb yuav yog qhov tseem ceeb rau kev tsim cov tshuaj tiv thaiv kab mob, qhov tseem ceeb ntawm T hlwb hauv kev txo cov kab mob hnyav kuj tseem ceeb dua nyob rau hauv cov xwm txheej uas cov tshuaj tiv thaiv cov tshuaj tiv thaiv txo qis los yog tseem tsis tau pom. Thaum ntxov induction ntawm SARS-CoV-2-T cells tshwj xeeb tau pom ntau zaus hauv cov kab mob me dua li cov kab mob hnyav107, thiab CD{13}}T cells yuav yog qhov tseem ceeb tshwj xeeb hauv kev txo cov txiaj ntsig loj hauv cov neeg mob B cell deficiency108. Tsis tas li ntawd, ib qho kev ua haujlwm siab CD8+ T cell teb tau mob siab rau 1 lub lis piam tom qab thawj koob tshuaj mRNA BNT162b2 tshuaj tiv thaiv (Pfizer-BioNTech), nyob rau lub sijhawm uas tsis muaj cov tshuaj tiv thaiv kab mob tsis zoo, ua rau muaj qhov ua tau tias cov tshuaj tiv thaiv ntxov- Induced tiv thaiv tej zaum yuav yog feem ntau nyob ntawm T cells109.
Daim duab 1|Cov khoom ntawm cov amino acid hloov pauv lossis tshem tawm hauv SARS-CoV-2 cov kev txhawj xeeb
Muab lub luag haujlwm tseem ceeb ntawm T cell hauv SARS-CoV-2 kev tiv thaiv, lub peev xwm muaj nyob rau hauv kev xaiv lub siab kom ua rau T cell khiav tawm, txawm hais tias qhov twg SARS-CoV-2 kev hloov pauv cuam tshuam rau T hlwb tam sim no. nkag siab tsis zoo. Cov lus teb ua haujlwm T cell yog qhia tawm tsam ntau tus kab mob proteins, nrog rau qhov loj ntawm cov lus teb cuam tshuam nrog cov kab mob protein qhia qib. Teb rau spike protein, N protein, thiab M protein dominate, nrog cov lus teb txaus siab kuj pom tawm tsam ORF3a thiab cov proteins uas tsis yog qauv NSP3 thiab NSP12 (ref. 110). Raws li T cell teb lub hom phiaj ntawm epitopes thoob plaws SARS-CoV-2 genome, cov hneev taw ntawm T cell khiav tawm tau nthuav dav ntau dua li cov kev hloov pauv ntawm cov tshuaj tiv thaiv kab mob, uas yog cov concentrated nyob rau hauv cov epitopes tseem ceeb ntawm cov protein ntau (Fig. 3) . Ob peb txoj kev tshawb fawb tau sau tseg qhov kev hloov pauv ntawm intrahost hauv T cell epitopes, uas yuav ua pov thawj ncaj qha ntawm T cell khiav tawm. Kev hloov pauv hauv CD8+ epitopes hauv N protein (M322I thiab L331F), M protein (L90F), thiab spike protein (L270F) tau raug sau tseg nyob rau hauv cov haiv neeg tsawg hauv ib txoj kev tshawb fawb thaum kis mob hnyav, ua rau poob ntawm epitope tshwj xeeb. lus 111. Ntev SARS-CoV-2 kev kis kab mob hauv cov chaw tiv thaiv kab mob tiv thaiv kab mob tuaj yeem muab txoj hauv kev ntau dua rau T cell khiav, zoo li cov piv txwv piav qhia dav dav hauv HIV-1 kab mob112. Kev tshwm sim ntawm NSP3 T504P kev hloov pauv uas ua rau poob ntawm CD8+ epitope cov lus teb tau raug tshaj tawm hauv ntau tus neeg uas muaj lub cev tsis muaj zog tiv thaiv kab mob tab sis khaws cia cov lus teb T cell hauv cov ntsiab lus ntawm tus mob SARS-CoV-2 kab mob113, 114. Cov kev tshawb pom no tsuas yog txwv rau qee qhov xwm txheej, qhia tau tias yuav tsum tau muaj kev tshawb fawb ntxiv rau yav tom ntej hauv kev ntsuas kev pheej hmoo ntawm T-cell khiav tawm hauv qee cov neeg mob. Ntau qhov kev hloov pauv hauv immunodominant ORF3a thiab N protein CD8+ T cell epitopes uas ua rau tsis muaj kev lees paub tau tshwm sim ntawm nws tus kheej hauv ntau yam SARS-CoV-2 kab mob115. Ntawm cov no yog N protein P13L, tam sim no hauv Omicron hauv B*27:05 txwv CD8+ epitope. Muab qhov kev xav tias VOCs tshwm sim nyob rau hauv cov kab mob ntev, nws yog kev ntxias kom xav tias muaj P13L nyob rau hauv Omicron VOC qhia txog kev xaiv vim T cell siab thaum lub sij hawm kis kab mob, ntxiv rau cov hnub qub ntawm kev hloov pauv uas yuav ua rau muaj kev cuam tshuam los ntawm cov tshuaj tiv thaiv. . L452R pom hauv Delta, Epsilon, Kappa, thiab BA.4/ BA.5 variant spike proteins ua rau poob ntawm A*24:02- txwv CD8+ teb116. Qhov kev hloov pauv P272L tau tshwm sim hauv ntau hom kab thoob ntiaj teb, thiab ua rau poob ntawm HLA A*02:01 txwv CD8+ epitope117. Lub luag haujlwm uas T hlwb muaj nyob rau hauv kev tsav tsheb qhov kev hloov no, ntxiv rau cov tshuaj tiv thaiv evasion thiab txhim kho ACE2-binding affinity, yog tsis paub tseeb. Lwm qhov kev hloov pauv loj hauv VOCs uas tau cuam tshuam nrog kev poob ntawm CD tshwj xeeb 4+ cov lus teb suav nrog L18F, D80A, thiab D215G hauv Beta, thiab D1118H hauv Alpha118,119. Cov qib uas cov kev soj ntsuam no kuj sawv cev qhov teeb meem tshwm sim ntawm T cell teb nrog kev hloov pauv uas tau tsav los ntawm lwm yam kev ntxhov siab tam sim no tsis paub. Txawm hais tias poob ntawm cov lus teb tshwj xeeb no, ntau qhov kev tshawb fawb qhia tau tias tag nrho T-cell cov lus teb cuam tshuam los ntawm kev kis kab mob thiab cov tshuaj tiv thaiv thawj tiam yog khaws cia tiv thaiv feem ntau VOCs105,118-120. Txawm hais tias qhov kev hloov pauv loj hauv Omicron spike protein ua rau tsuas yog qis dua 30% txo qis hauv tag nrho CD4+ thiab CD8+ cov lus teb, nrog rau kev sib txawv ntawm ib tus neeg ntau dua 119,120. Feem ntau cov kab mob siab tshaj plaws CD4+ cov lus teb epitope yog tsom rau thaj tsam tsis sib xws ntawm NTD, carboxy terminus, thiab fusion protein cov cheeb tsam, nrog tsawg heev hauv RBD110. Tsis muaj qhov tseeb hotspots ntawm spike CD8+ epitopes110. Kev hloov pauv siab nyob rau hauv qhov loj RBD thiab NTD pom nyob rau hauv ntau VOCs uas xav tias yuav tsum tau tsav los ntawm cov tshuaj tiv thaiv kab mob evasion thiab nce ACE2-binding affinity tej zaum yuav muaj kev cuam tshuam rau tag nrho T-cell teb. Yog li, feem ntau T cell epitopes tau khaws cia hauv VOCs sib txawv, thiab qhov no yuav ua rau muaj txiaj ntsig zoo rau cov tshuaj tiv thaiv kev tiv thaiv kev mus pw hauv tsev kho mob thiab tuag nrog Omicron pom tom qab koob thib ob thiab tom qab koob thib peb thaum piv nrog tsis muaj tshuaj tiv thaiv121. Lwm qhov laj thawj tseem ceeb rau qhov cuam tshuam me me ntawm kev sib txawv ntawm T cell tiv thaiv yog qhov dav ntawm cov lus teb tsim, nrog rau txhua cov lus teb txuas mus rau 30-40 epitopes tom qab kis kab mob 110. Ntawm cov pejxeem, tseem muaj ntau dua heterogeneity nyob rau hauv T cell teb dua li cov tshuaj tiv thaiv kab mob vim muaj ntau yam polymorphisms nyob rau hauv tib neeg HLA noob. Ntawm ib tus neeg, txawm li cas los xij, qhov txo qis hauv qhov tshwj xeeb CD8+ cov lus teb rau Omicron tau tshaj tawm txog ~ 15% ntawm cov neeg mob ntshav qab zib thiab cov tshuaj tiv thaiv pub dawb117, nrog rau lwm txoj kev tshawb fawb sau tseg ntau dua 50% poob ntawm CD{{88} } T cell thiab CD8+ T cell teb nyob rau hauv ~ 20% ntawm cov tib neeg kuaj122. Txawm hais tias qhov dav dav ntawm cov txiaj ntsig tau raug txwv los ntawm cov qauv me me thiab HLA kev faib tawm ntawm cov pej xeem tau kawm, txawm li cas los xij qhia txog qhov muaj feem cuam tshuam ntawm VOCs ntawm T-cell cov lus teb hauv qee cov tib neeg uas muaj kev tiv thaiv kab mob tshwj xeeb tsuas yog tsim los ntawm kev txhaj tshuaj. Nws zoo nkaus li tias kev khiav tawm ntawm cov tshuaj tiv thaiv kab mob thiab kev sib kis tau zoo yuav ua rau muaj kev tsav tsheb ntau dua ntawm VOCs tshaj qhov tseem ceeb ntawm T-cell khiav tawm. Txawm hais tias peb yuav pom qhov poob qis thiab ua ntu zus ntawm CD8+ epitopes dhau sijhawm, zoo ib yam li kev hloov mus sij hawm ntev hauv kab mob khaub thuas H3N2, nyuaj rau kwv yees97. T cell khiav tawm tuaj yeem tshwm sim los ntawm ntau lub tshuab98. Amino acid hloov nyob rau hauv epitopes los yog flanking cheeb tsam tuaj yeem cuam tshuam kev ua cov tshuaj antigen, thiab kev hloov pauv rau cov khoom seem tuaj yeem cuam tshuam nrog loj histocompatibility complex (MHC) khi rau epitopes123. Ob lub tshuab no tuaj yeem ua rau tsis tuaj yeem poob ntawm T cell teb rau ib qho epitope. Cov kev hloov pauv uas cuam tshuam T cell receptor khi rau peptide-MHC complex tuaj yeem, los ntawm qhov sib txawv, ua rau muaj kev khiav tawm ib nrab lossis ua tiav. Qhov xwm txheej tom ntej no kuj tseem tuaj yeem kov yeej los ntawm de novo T cell teb siv lwm T cell receptor repertoires, raws li tau piav qhia yav dhau los hauv HIV{102}} kab mob124.
Raws li qhov muaj peev xwm T cell khiav tawm, SARS-CoV-2, zoo li ntau lwm cov kab mob, ncaj qha downregulates MHC class I (MHC-I) qhia ntawm cov kab mob kis mus rau evade T cell paub, zoo tshaj piav qhia rau cov khoom siv protein ORF8 ( ref. 125, 126). ORF7a (nrog rau ORF3a thiab ORF6 (refs. 127,128)) kuj tau tshaj tawm rau downregulate MHC-I (refs. 128,129), txawm hais tias nws tsis paub meej tias qhov no yog ib qho txiaj ntsig tshwj xeeb lossis tsuas yog qhov tshwm sim ntawm nonspecific Golgi fragmentation130. Kev ua haujlwm tsis ntev los no tau pom tias cov kev hloov pauv uas pom hauv VOCs tsis hloov lub peev xwm ntawm ORF8 txhawm rau txhawm rau MHC-I kev qhia, tshwj tsis yog kev tso tseg ntxov ntxov ntawm codon ntawm amino acid 27 hauv Alpha, uas ua rau kev nthuav tawm ntawm daim ntawv truncated, tsis ua haujlwm ntawm ORF8. (saib. 126,131). Txawm hais tias qhov kev txiav tawm ntawm ORF8, nyob rau hauv cov ntsiab lus ntawm kev kis tus kab mob, Alpha tseem txo qis MHC-I kev qhia, txhais tau tias qhov kev hloov pauv no, lossis tejzaum nws yog SARS-CoV-2 feem ntau, tau hloov kho cov txheej txheem rov ua dua los tiv thaiv txoj kev no126.
Daim duab 2|Furin cleavage site thiab variant kev vam meej
Innate immunity and SARS-CoV-2 variants
Innate tiv thaiv kab mob yog ib feem tseem ceeb ntawm tus tswv tsev tiv thaiv kab mob, nrog rau lub luag haujlwm tseem ceeb hauv kev tiv thaiv kab mob thaum ntxov thiab kho cov tshuaj tiv thaiv kab mob. Cov tshuaj tiv thaiv kab mob hauv lub cev yog qhov tseem ceeb tshwj xeeb rau cov kab mob tshiab, xws li cov kab mob zoonotic, uas feem ntau tsis muaj kev tiv thaiv kab mob ua ntej. Nws yog qhov xav tsis thoob thaum cov kab mob zoonotic tshiab muaj txiaj ntsig zoo ntawm kev sib kis ntawm tib neeg los ntawm kev tawm tsam zoo ntawm kev tiv thaiv tus tswv tsev, txawm hais tias tsis ntev los no ua tiav kev rov ua dua tshiab thiab kev sib kis nyob rau hauv ib hom kab mob sib txawv, nrog rau nws feem ntau sib txawv innate tiv thaiv kab mob. Qhov tshwm sim ntawm qhov muaj zog ntawm tib neeg lub cev tiv thaiv kab mob yog qhov feem ntawm cov kab mob zoonotic uas ua rau muaj kev sib kis tsis tshua muaj qis, thiab cov khoom uas hloov zuj zus hauv SARS-CoV-2 hom reservoir, tshwj xeeb tshaj yog cov tswv tsev tropism ( uas tshwm sim suav nrog tib neeg) ua ke nrog kev nrhiav tau ntawm nws FCS nyob rau hauv cov kab mob sib kis, tejzaum nws yog ib hom kab mob nruab nrab, yog cov yam ntxwv tseem ceeb rau kev pib COVID-19 kev sib kis. Nws yog ib qho tseem ceeb uas tus kab mob SARS muaj feem xyuam nrog SARS-CoV tsis tau tsim nws tus kheej hauv tib neeg cov pej xeem, txawm hais tias tseem kis tau zoo heev, nws qhov kev tshem tawm tau raug ntaus nqi qis dua asymptomatic kis piv nrog SARS-CoV-2, ua kom yooj yim txheeb xyuas. kab mob. Qhov tseem ceeb, raws li SARS-CoV-2 VOCs tau tshwm sim, nws tau pom tseeb tias lawv tau txais kev hloov kho kom muaj txiaj ntsig zoo rau tib neeg, thiab qhov no yog ib feem yog los ntawm kev txhim kho lub cev tiv thaiv kab mob. Tseeb tiag, Alpha133,134 thiab VOCs77,135,136 tsis ntev los no tau hloov zuj zus txo kev nkag siab zoo rau cov interferons, raws li qhov no yog qhov tseem ceeb ntawm kev xaiv tus kab mob kis rau tib neeg. Kuj ceeb tias, ntau dua li kev hloov kho tshwj xeeb rau tib neeg cov proteins, Alpha thiab Omicron sublineages BA.4 thiab BA.5 muaj ib feem ua tiav qhov no los ntawm kev txhawb nqa kev qhia txog kev tiv thaiv kab mob hauv lub cev tiv thaiv kab mob, tshwj xeeb tshaj yog cov protein ORF6 (ref. 77). ORF6 inhibits kev thauj mus los ntawm cov khoom siv hluav taws xob, suav nrog STAT1 thiab IRF3 (ref. 137), uas tswj cov kev qhia ntawm cov tshuaj tiv thaiv kab mob thiab cov tshuaj tiv thaiv kab mob soluble. Alpha kuj tau txhim kho kev qhia ntawm ORF9b (uas inhibits signaling downstream ntawm RNA sensing138) thiab N protein (uas sequesters viral RNA los tiv thaiv kev ua kom lub cev sensing mechanisms98), nrog rau de novo qhia ntawm N * / N.iORF3 - cov amino-terminally truncated daim ntawv ntawm N protein, uas qhia ib co interferon antagonism tab sis yog qhia nyob rau hauv qis theem 98. Kev nce qib ntawm cov proteins no zoo li qhov tshwm sim ntawm kev hloov pauv hauv cheeb tsam tswj hwm uas hloov pauv subgenomic RNA synthesis thiab qhia cov protein. Qhov no qhia txog qhov tseem ceeb ntawm kev hloov pauv sab nraud ntawm cov protein ntau hauv kev txiav txim siab VOC cov khoom, tshwj xeeb hauv cov cheeb tsam tswj hwm. Qhov tseem ceeb, kev hloov pauv hauv N protein Kozak ib ntus uas xav tias yuav cuam tshuam rau kev qhia ntawm Alpha N protein thiab cov protein sib tshooj ORF9b kuj tshwm sim hauv VOCs Delta thiab Omicron, tab sis lawv tag nrho cov kev cuam tshuam rau lub cev tsis muaj zog tiv thaiv kab mob hauv cov VOCs tseem yuav txiav txim siab. . Kev sib raug zoo ntawm SARS-CoV-2 thiab innate immunity yog qhov nyuaj heev. Piv txwv li, tus kab mob antagonist ORF9b zoo li tau tswj tsis zoo los ntawm phosphorylation los ntawm tus tswv kinases, qhia tias nws lub cev tiv thaiv kab mob tuaj yeem raug hloov mus rau qee lub sijhawm thaum kis kab mob, tej zaum ib zaug cov lus teb tus tswv tau tshwm sim hauv cov kab mob 133. Xws li ib qho kev hloov pauv hloov pauv, uas tseem ceeb tswj hwm tus tswv teb rau kev kis tus kab mob, tuaj yeem tsav cov tsos mob thiab kis tus kab mob tom qab los ntawm kev hloov pauv cellular activation.
Yam tsawg kawg 15 SARS-CoV-2 cov proteins tau raug qhia los pab txhawb rau kev tawm tsam ntawm cov lus teb hauv lub cev rau hnub tim (saib xyuas kom meej rau lwm qhov 139,140). Cov proteins no feem ntau tau txheeb xyuas los ntawm cov ntawv xov xwm cov ntxaij vab tshaus uas SARS-CoV-2 cov protein ntawm kev txaus siab tau qhia thaum lub sij hawm simulated hauv vitro innate lub cev tiv thaiv kab mob thiab nws lub peev xwm los tawm tsam cov lus teb raug tshuaj xyuas. Cov kev sim no feem ntau tsis muab kev pom kev siv tshuab tab sis muaj txiaj ntsig zoo hauv kev tshawb nrhiav cov haujlwm tshiab protein. Ob peb ntawm VOCs nthuav tawm cov amino acid hloov pauv hauv ntau cov proteins uas cuam tshuam rau hauv lub cev tiv thaiv kab mob, suav nrog NSP1, NSP3, NSP6, ORF3a, ORF6, ORF7b, ORF8, thiab N protein. Txawm hais tias cov coding kev hloov pauv no cuam tshuam txog kev hloov pauv kom zoo dua rau kev tiv thaiv tib neeg lub cev tiv thaiv kab mob tseem tsis tau tsim nyob rau hauv feem ntau.
Ntxiv mus, qhov kev koom tes ntawm cov proteins no rau VOC phenotype tsis to taub, vim qhov no yuav tsum muaj kev mob siab rau tiam ntawm isogenic mutants siv cov noob caj noob ces thim rov qab thiab kev ntsuam xyuas ntawm lawv cov kev cuam tshuam ntawm kev rov ua dua, interferon ntau lawm, thiab rhiab heev. Ntxiv nrog rau kev txo qis kev cuam tshuam ntawm interferon, Alpha thiab Omicron VOCs muaj kev tiv thaiv ntau dua rau inhibition los ntawm lawv cov tshuaj tiv thaiv kab mob 126,133–135,141. Qhov no tau piav qhia tau zoo tshaj plaws yog muaj feem xyuam nrog kev hloov pauv hloov pauv uas txo qis kev nkag siab ntawm interferon-induced transmembrane (IFITM) txwv tsis pub muaj 76,134,142. Cov nyhuv tiag tiag ntawm IFITM proteins thaum lub sij hawm SARS-CoV-2 replication yog qhov sib cav, nrog qee cov kev tshawb fawb qhia tias IFITM proteins inhibit cellular nkag ntawm SARS-CoV{11}}, zoo ib yam li influenza19,76,134,142, whereas lwm tus. qhia tias hauv qee qhov chaw lawv txhim kho kev kis kab mob, zoo ib yam li tau piav qhia rau OC43 thiab HKU1 (refs. 76,134,143–145). Lub luag haujlwm tseem ceeb ntawm IFITM cov proteins yuav yog cov ntsiab lus tshwj xeeb, xws li kev nkag mus siv tshwj xeeb los ntawm cov kab mob tshwj xeeb hauv ib hom xov tooj ntawm tes lossis kab xov tooj ntawm tes, kev siv cov kab mob muaj sia tiv thaiv kab mob pseudovirus, thiab qib ntawm IFITM protein qhia. Cov tswv cuab ntawm tsev neeg IFITM yog me me, interferon-stimulated transmembrane proteins uas cuam tshuam nrog cov cell membranes sib txawv; tib neeg IFITM1 feem ntau cuam tshuam nrog cov cell nto membranes, whereas IFITM2 thiab IFITM3 muaj ntau lub zos mus rau lig thiab ntxov endosomes, feem ntau 76,146. Lub ntsiab mechanism uas IFITM proteins cuam tshuam tus kab mob nkag tsis tau tag nrho daws, tab sis inhibition ntawm viral glycoprotein fusion nrog host membranes yog xav tias muaj kev koom tes147,148. Ob peb VOCs tau pom tias muaj ntau theem ntawm rhiab heev rau IFITM protein inhibition lossis txhim kho, feem ntau cuam tshuam nrog cov kev nkag tshwj xeeb lossis furin cleavage phenotypes. Piv txwv li, Omicron, uas muaj txiaj ntsig zoo ntawm kev nkag mus rau endosomal tshaj li qhov sib txawv thaum ntxov thiab lwm yam VOCs, zoo li pom tias muaj kev cuam tshuam ntau dua (lossis qee qhov kev txhim kho) los ntawm endosomal IFITM proteins, txawm hais tias qhov no tshwm sim los ntawm kev siv ntawm tes siv32, 76,145 ib. Qhov no tuaj yeem yog vim Omicron txawm tias yuav tsum muaj kev cuam tshuam los ntawm innate evasion vim kev tiv thaiv kev tiv thaiv kab mob, tshwj xeeb tshaj yog nyob rau hauv cov ntsiab lus ntawm kev txhaj tshuaj tiv thaiv kab mob los yog yuav tsum tau hloov mus siv IFITM proteins ua cofactors rau kev nkag. Nws tseem tsis tau paub meej tias kev txhim kho kev tawm tsam ntawm lub cev tiv thaiv kab mob tuaj yeem cuam tshuam tus kab mob kis tau li cas. Peb xav tias qhov muaj peev xwm ntawm SARS-CoV-2 kom kis tau zoo yog txuas nrog nws lub peev xwm los khiav tawm thiab tiv thaiv lub cev tiv thaiv kab mob hauv thawj lub hlwb uas ntsib tus kab mob hauv txoj hlab pa. Tseeb tiag, qhov ua tau zoo ntawm cov xwm txheej kis tau zoo yuav tsum cuam tshuam tus kab mob kis los ntawm txoj hlab pa thiab yog li qhov yuav tshwm sim ntawm kev cog qoob loo ntawm kev kis tus kab mob txhua. Hom I interferon cov lus teb tau pom tias yog ib qho tseem ceeb hauv kev txiav txim siab kev kis tus kab mob thiab qhov tshwm sim rau lwm yam kab mob, thiab tau ua tus cwj pwm zoo rau tus kab mob lentiviral ntawm macaques149.
Thaum kawg, qhov tseeb tias tam sim no txhua VOC tau hloov pauv ntawm nws tus kheej los ntawm tus kab mob poj koob yawm txwv uas tshwm sim thaum muaj kev sib kis thoob ntiaj teb txhais tau hais tias txhua VOC tau coj txoj hauv kev sib txawv kom tau txais kev hloov pauv rau tib neeg. Raws li qhov tshwm sim, VOCs, lossis qhov tseeb ntawm lwm yam kev hloov pauv ntawm SARS-CoV-2, tuaj yeem rov ua dua los sib sau ua ke ntawm nws tus kheej hloov pauv hloov pauv thiab yog li cov txiaj ntsig zoo ntawm cov genomes sib txawv (Box 2).
Daim duab 3|Tej yam tshwm sim ntawm SARS-CoV-2 variants ntawm T cell teb thiab innate immunity.
Antigenic nrug nyob rau hauv kev txiav txim kis tau tus mob thiab lub zog
Kev hloov pauv ntawm cov pej xeem kev tiv thaiv ib puag ncig tsim kom muaj lub zog muaj zog rau cov kab mob sib txawv vim tias lawv lub cev muaj zog ntau npaum li nyob ntawm kev tiv thaiv kev tiv thaiv ib yam li ntawm lawv cov kev hloov pauv tshwj xeeb. Txawm hais tias qhov nyuaj xws li qhov dav thiab ntev ntawm kev tiv thaiv kab mob yog qhov tseem ceeb rau kev txiav txim siab150,151, cov neeg coob coob tau kis tus kab mob SARS-CoV-2, los ntawm kev kis kab mob thiab / lossis tshuaj tiv thaiv, ua rau cov pej xeem tsis tshua muaj kev cuam tshuam rau feem ntau ntawm kev ncig ( thiab yav dhau los) cov kev hloov pauv uas muaj tsawg zuj zus ntawm cov neeg tsis muaj zog tiv thaiv kab mob, ua rau muaj kev cuam tshuam tag nrho (Fig. 4). Thaum ntxov ntawm COVID-19 kev kis thoob qhov txhia chaw, thaum feem ntawm cov neeg tsis paub lus yog qhov loj tshaj, muaj qhov kev hloov pauv me ntsis ntawm cov tshuaj antigenic tshiab txheeb ze rau cov tsiaj qus. Hloov chaw, xaiv cov kev hloov pauv uas muaj peev xwm ua kom muaj kev loj hlob zoo los ntawm kev hloov pauv ntawm cov kab mob hauv nruab nrog cev xws li kev hloov pauv hauv cov kab mob sib kis los ntawm D614G, kev hloov pauv ntawm PANGO kab B.1, lossis kev txhim kho furin cleavage phenotype ua ke nrog nce ACE2 khi. nthuav tawm los ntawm Alpha27,29. Raws li kev tiv thaiv kab mob hauv cov neeg pej xeem tau nce ntxiv, qhov sib txawv ntawm cov tshuaj antigenic novelty tau ua lub luag haujlwm tseem ceeb hauv nws txoj kev loj hlob zoo, txheeb ze rau kev hloov pauv hauv lub cev 152. Tom qab ntawd, Delta VOC tau dhau los ua qhov tseem ceeb hauv ntiaj teb, hloov pauv cov hloov pauv yav dhau los hauv cov tebchaws uas muaj cov neeg tiv thaiv kab mob ib nrab nrog cov tshuaj tiv thaiv nruab nrab mus rau siab tshaj 23,153. Cov ntaub ntawv hais txog tus kab mob neutralization qhia tau hais tias lub cev tsis muaj zog tiv thaiv kab mob los ntawm cov tshuaj tiv thaiv kab mob tsis zoo los ntawm Delta VOC23,37-39, thiab cov ntaub ntawv tshuaj tiv thaiv tau qhia tias cov tshuaj tiv thaiv tshiab tsis yog thawj tus neeg tsav tsheb ntawm kev sib kis ntau ntxiv 40-42,154,155, qhia tias lub cev muaj zog ntawm Delta yog ntau qhov tshwm sim ntawm intrins. Viral zog xws li optimization ntawm spike furin cleavage22,23,69. Piv nrog rau cov kev hloov pauv dhau los, Omicron tau pom qhov tsis tau pom dua ntawm cov tshuaj antigenic novelty31,33,34, sib cav piv rau tus mob khaub thuas zoo li antigenic hloov kev tshwm sim51. Qhov 'hloov' ntawm no, kev sib txuam ntawm kev hloov pauv uas ua rau muaj qhov sib txawv ntawm cov tshuaj tiv thaiv kab mob, tej zaum yuav tshwm sim tsawg kawg yog ib feem ntawm cov ntsiab lus ntawm kev kis kab mob los yog kab mob ntev (Box 1). Kev sib piv ntawm kev sib kis tau zoo nyob rau hauv cov tsev neeg uas tau txhaj tshuaj tiv thaiv thiab tsis muaj tshuaj tiv thaiv tau qhia tias kev tiv thaiv kev tiv thaiv yog ib qho tseem ceeb ntawm kev sib kis ntawm Omicron (BA.1) txheeb ze rau Delta thaum lawv lub sij hawm sib koom ua ke 86.
Daim duab 4|Dominant SARS-CoV-2 variants, txhaj tshuaj tiv thaiv, kis kab mob, thiab tuag txij thaum ntxov 2020 hauv UK
Omicron sublineage BA.2 tau ua pov thawj tias muaj peev xwm kis tau rau ob tus neeg tsis tau txhaj tshuaj thiab txhaj tshuaj tiv thaiv kab mob, uas muaj feem cuam tshuam los ntawm kev tiv thaiv kab mob tiv thaiv kab mob zoo ib yam li cov BA.1 tab sis muaj ntau dua intrinsic transmissibility156. Tsis ntev los no BA.4, BA.5, BA.2.75 thiab lawv cov sublineages tau pom tias tsis yog tsuas yog muaj kev tiv thaiv kev tiv thaiv ntau dua li cov tshuaj tiv thaiv ua ntej Omicron tab sis kuj khiav tawm ntawm kev tiv thaiv kab mob los ntawm kev kis kab mob ua ntej nrog Omicron, tshwj xeeb tshaj yog BA.1 (refs. 46). — 49, 157–159). Qhov no tau raug ntaus nqi rau kev hloov pauv ntawm antigenically muaj zog RBD txoj haujlwm, tshwj xeeb tshaj yog L452R thiab F486V hauv qhov piv txwv ntawm BA.4/ BA.5 (ref. 160). Txawm hais tias tej zaum yuav tseem muaj peev xwm ua kom tau zoo ntxiv ntawm SARS-CoV{19}} rau kev sib kis hauv tib neeg, tam sim no zoo li tias qhov tshuaj tiv thaiv kab mob tshiab thiab kev tiv thaiv kab mob tsis zoo ntawm cov kev hloov pauv tshiab yuav yog thawj qhov kev txiav txim siab ntawm kev sib txawv ntawm kev tawm dag zog thiab kev vam meej mus tom ntej. . Yog li ntawd, kev nkag siab txog qhov nyuaj ntawm kev tiv thaiv kev sib txawv ntawm kev sib txawv yog qhov tseem ceeb ntawm kev tshawb fawb.
Relative severity of SARS-CoV-2 variants
Nws yog ib qho tseem ceeb kom nkag siab tias yuav ua li cas kev ua phem ntawm SARS-CoV-2 variants yuav hloov zuj zus los teb rau kev hloov pauv kev xaiv. Pathogen virulence, nrog rau kev tiv thaiv kab mob, kev tiv thaiv tus kheej, kab mob predisposition, thiab lwm yam kev koom tes, yog ib qho tseem ceeb rau kev mob hnyav thiab tau txhais nyob rau hauv cov ntaub ntawv evolutionary raws li qhov nce morbidity thiab tuag ntawm cov tib neeg vim yog kab mob. Virulence tsis tas yuav txo qis nrog lub sijhawm hauv cov pej xeem hauv tsev, theej, qauv cov ntaub ntawv feem ntau qhia txog kev sib pauv ntawm tus nqi sib kis thiab virulence161,162. Txawm li cas los xij, qhov kev twv ua ntej ntawm kev ua phem evolution yog qhov nyuaj los ntawm ntau lub tswv yim, nrog rau kev sib tw hauv-tus tswv tsev, hloov txoj kev sib kis thiab tropism, thiab kev cuam tshuam nrog lub cev tiv thaiv kab mob. Piv txwv li, rov kis tus kab mob tsis zoo, tus yam ntxwv ntawm cov kab mob antigenically hloov zuj zus tuaj, tuaj yeem xaiv cov kab mob siab dua 163. Kev ntsuam xyuas tus txheeb ze ntawm tus kab mob SARS-CoV-2 qhov sib txawv los ntawm cov kab mob hnyav hauv tib neeg yog qhov nyuaj vim hloov lub cev tiv thaiv kab mob thiab kev txhim kho hauv kev kho mob thoob plaws ntiaj teb, txawm hais tias nws muaj peev xwm los sib piv cov kab mob hnyav ntawm cov kab mob sib txawv uas kis tau zoo ib yam. cov neeg nyob rau hauv ib lub sij hawm muab 164. Txoj hauv kev no qhia txog qhov tsis sib xws hauv kev coj ntawm kev hloov pauv ntawm cov kab mob hnyav ntawm kev ua tiav tseem ceeb ntawm SARS-CoV-2 variants: cov kev hloov pauv tau zoo tau nthuav tawm cov kab mob ntau ntxiv raws li Alpha hloov B.1.177, thiab raws li Delta hloov Alpha, cuam tshuam nrog cov txheeb ze hloov pauv hauv transmissibility164. Los ntawm qhov tsis sib xws, Omicron tau nthuav tawm txo cov kab mob hnyav nyob rau lub sijhawm uas nws koom nrog Delta, qhov txo qis uas zoo li muaj kev cuam tshuam nrog kev sib xyaw ua ke nrog rau ob qho tib si kev kis tus kab mob ntau dua ntawm cov neeg uas muaj qee qhov kev kis tus kab mob ua ntej thiab qhov qis qis hauv qhov virulence164- 168. Cov lus piav qhia rau cov kab mob qis qis ntawm Omicron kab mob suav nrog txo fusogenicity ntawm cov kab mob sib kis, ua rau cov ntaub so ntswg puas tsawg, thiab hloov tropism txwv ntau rau cov kab mob ua pa (vim hloov TMPRSS2 siv) 32,75,78,79. Cov kev tshawb fawb yav dhau los no tau muab piv rau cov kab mob sib txawv uas muaj nyob hauv tib cov pej xeem, txawm hais tias lawv tsis tuaj yeem txiav txim siab 'intrinsic' virulence ntawm non-overlapping variants uas tau nthuav tawm hauv cov neeg uas muaj kev tiv thaiv kab mob sib txawv, xws li Alpha thiab Omicron. Muab hais tias kev tiv thaiv kab mob ntawm ib tus neeg cuam tshuam rau qhov hnyav ntawm cov tsos mob ntxiv rau qhov yuav kis tau tus kab mob, antigenic 'nruab deb' ntawm yav dhau los raug thiab qhov sib txawv ntawm qhov sib txawv muaj peev xwm los pab txhawb qhov pib ntawm tus kab mob hauv lwm tus neeg tiv thaiv, sawv cev rau muaj peev xwm rau kev sib txawv ntawm qhov muaj peev xwm ua rau muaj kev phom sij thiab kev ua phem tiag tiag hauv cov neeg muaj mob.
Lub thawv 3
Fitness thiab antigenicity
Darwinian Fitness209, feem ntau hu ua 'kev qoj ib ce', yog qhov txawv ntawm qhov kev ua kom zoo dua qub: lub peev xwm ntawm tus kab mob los tsim cov kab mob sib kis, ntsuas kev sim hauv cov kab lis kev cai, hauv cov kab lis kev cai, lossis hauv ib tus tswv tsev 210,211. Los ntawm qhov sib txawv, cov ntsiab lus dav dav ntawm kev qoj ib ce yog kev ua tiav ntawm kev yug me nyuam yog li nws yog cov ntsiab lus tseem ceeb-dependant feem ntau sib txawv raws sijhawm thiab ntawm qhov chaw. Lub zog ntawm tus mob hnyav ua pa nyuaj ua rau tus mob coronavirus 2 (SARS-CoV-2) variant yuav nyob ntawm qhov hloov pauv ntawm lub cev tiv thaiv kab mob ntawm cov neeg nyob hauv uas nws tab tom ncig, thiab kev vam meej ntawm tus neeg sib txawv yog txheeb ze rau cov khoom ntawm kev sib tw variants nyob rau hauv tus kab mob cov pej xeem thiab stochastic sampling txheej txheem. Raws li kev tiv thaiv kab mob hauv cov neeg pej xeem nce, cov xwm txheej tuaj yeem ua rau muaj qhov hloov pauv tau dhau los, xws li hauv cov neeg tsis muaj zog tiv thaiv kab mob, tam sim no tsis tshua haum rau ntau qhov hloov pauv (Fig. 4b). Txawm hais tias intrinsic transmissibility yog li no raws li cov khoom lom neeg ntawm tus kab mob nkaus xwb, qhov tseeb kis tau nyob ntawm cov khoom no hauv cov ntsiab lus ntawm kev tiv thaiv pej xeem, suav nrog kev sib cuam tshuam ntawm tus tswv tsev tiv thaiv los ntawm yav dhau los raug, variant antigenicity, thiab stochastic cuam tshuam. Ntxiv mus, txawm hais tias nws muaj peev xwm sib txawv ntawm lawv cov txheeb ze antigenicity - theem ntawm lub cev tiv thaiv kab mob lawv txhawb nqa - kev sib txawv ntawm qib ntawm antigenic zoo sib xws rau lwm yam sib txawv yog feem ntau cuam tshuam ntau dua. Raws li kev tiv thaiv kab mob hauv cov neeg pej xeem nce, cov tshuaj tiv thaiv kab mob sib txawv ntawm qhov sib txawv mus rau yav dhau los cov kab sib txawv tuaj yeem txiav txim siab nws lub peev xwm kis tau, rov ua dua, thiab sib kis ntawm cov tswv. Lub evolution ntawm antigenic novelty yog li ntawd dhau los ua qhov tseem ceeb ntawm kev txiav txim siab ntawm kev sib txawv ntawm kev yug me nyuam thiab kev noj qab haus huv.
Ib txoj hauv kev ntxiv rau kev ntsuas ntsuas qhov muaj peev xwm ntawm SARS-CoV-2 kev hloov pauv suav nrog kev siv tsiaj cov qauv (saib qhov tob dua yav dhau los cov qauv tsiaj tau suav nrog cov nas tsis paub, xws li cov nas transgenic qhia txog tib neeg ACE2 nyob rau hauv kev tswj hwm ntawm keratin 18 txhawb nqa ( nthuav tawm ntau nyob rau hauv epithelial cells170) lossis hamsters, uas nws ib txwm qhia ACE2 cov proteins tau siv tau zoo los ntawm txhua qhov tam sim no SARS-CoV-2 VOCs32,171. Cov kab mob hauv cov qauv nas no feem ntau ntsuas raws li kev ua haujlwm ntawm feem pua ntawm qhov hnyav, qee zaum Nrog rau kev siv txoj kev ciaj sia taus thiab kev ntsuas ntawm cov qauv pulmonary muaj nuj nqi ntau dua cov ntaub ntawv sib npaug sib npaug los ntawm kev tshawb fawb txog kev kis kab mob hauv tib neeg, xws li Delta yog cov kab mob ntau dua li cov qauv ua ntej thiab Omicron tsis tshua muaj kab mob ntau dua Delta32,69,75,173,174. Txawm li cas los xij, cov qauv muaj. ob peb qhov kev txwv, raws li ua piv txwv los ntawm cov pov thawj kev kis kab mob tsis ntev los no los ntawm Hong Kong qhia tias Omicron sublineage BA.2 qhia txog tus kab mob hnyav zoo ib yam li thawj-yoj variants175, thaum cov qauv nas feem ntau qhia tias Omicron tsis hnyav dua li yav dhau los variants32,75,173,174,176. Qhov kev tsis sib haum xeeb no tuaj yeem piav qhia los ntawm kev hloov kho txuas ntxiv ntawm SARS-CoV-2 rau tib neeg cov tswv, ua rau muaj kev sib haum xeeb ntawm cov nas thiab lwm yam tsiaj qauv32,80,177,178. Kab mob hnyav tom qab SARS-CoV-2 kev kis kab mob muaj feem cuam tshuam nrog ntau yam kev pheej hmoo, suav nrog hnub nyoog siab, txiv neej kev kho mob morbidities xws li rog rog thiab tiv thaiv kab mob, thiab ntau yam kab mob inflammatory 179. Raws li kev tshuaj xyuas lwm qhov, ntau qhov kev tshawb nrhiav caj ces tsis ntev los no tau tsom mus rau cov yam ntxwv uas yuav piav qhia tias vim li cas qee tus neeg muaj kev pheej hmoo ntau dua rau SARS-CoV-2 kab mob thiab lwm tus muaj cov tsos mob hnyav dua. Txawm li cas los xij, muaj qhov xav tau ceev nrooj los muab cov kev tshawb pom no nrog cov ntaub ntawv los ntawm cov kev hloov pauv tshwj xeeb thiab kev cuam tshuam (uas yog, tshuaj tiv thaiv, tshuaj, thiab monoc, thiab monoclonal antibodies) uas tuaj yeem cuam tshuam ncaj qha rau cov phenotypes179. Tsis tas li ntawd, txawm hais tias qhov tshwm sim feem ntau thiab ntsuas tau yooj yim los ntawm kev kis mob hnyav yog pw hauv tsev kho mob lossis tuag, cov txiaj ntsig uas nyuaj rau ntsuas kuj tseem txawv ntawm ntau yam sib txawv, xws li cov tsos mob thawj zaug 181 lossis tom qab mob COVID-19 syndrome, txawm hais tias cov no yuav muaj. txawv heev los ntawm kev tiv thaiv kab mob ua ntej thiab.
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
Xaus
SARS-CoV-2 tau kis tau 3 xyoos nyob rau hauv tib neeg cov pej xeem, kis ntau pua lab tus tib neeg. Nws tseem nyob, txawm li cas los xij, tus kab mob tshiab tib neeg uas txuas ntxiv hloov zuj zus thiab tau txais kev hloov pauv rau nws cov hom tshiab. Unprecedented SARS-CoV-2 genome sequence datasets generated thoob ntiaj teb tau nthuav tawm cov pov thawj ntawm kev hloov pauv tau zoo tshwm sim hauv lub sijhawm tiag tiag-lub sij hawm coj mus kuaj sim kom nkag siab zoo txog qhov tseem ceeb ntawm kev sib cuam tshuam ntawm tus kab mob thiab tus tswv tsev. Txawm hais tias peb muaj qhov kev nkag siab zoo tshaj plaws ntawm SARS-CoV-2 biology, tus kab mob kev nyab xeeb yog qhov muaj zog thiab muaj peev xwm ntawm SARS-CoV-2 kom kis tau, rov ua dua hauv, thiab sib kis, d ntawm tib neeg cov pej xeem tau vam khom. qhia meej txog cov ntsiab lus tiv thaiv kab mob tshwj xeeb ntawm lub sijhawm sib txawv ntawm kev sib kis. Tam sim no, Omicron yog qhov tseem ceeb thoob ntiaj teb, nrog cov kab mob kis tau los ntawm kev tshwm sim BA.2 thiab BA.5 sublineages. Txawm hais tias peb txoj kev nkag siab ntawm SARS-CoV-2 tab tom txhim kho, kev hloov pauv tus kab mob yog qhov tshwm sim tsis tau pom dua, thiab qhov yuav tshwm sim yav tom ntej yog qhov tshwm sim ntawm VOC tshiab uas yog antigenically thiab, muaj peev xwm, phenotypically txawv ntawm cov qauv ntawm Omicron thaum ntxov. Nyob rau tib lub sijhawm, kev tiv thaiv pej xeem tiv thaiv SARS-CoV-2 txuas ntxiv mus ntxiv thiab tuaj yeem them rov qab zoo rau qhov kev hloov pauv yav tom ntej uas tshwm sim nrog qhov hnyav dua, ua rau mob hnyav dua. Txhua tus VOC progenitors tau hloov zuj zus los ntawm cov poj koob yawm txwv ua ntej-VOC tus kab mob tshwm sim thaum thawj nthwv dej ntawm kev sib kis, coj txawv tab sis feem ntau sib txuas txoj hauv kev kom muaj txiaj ntsig zoo dua thiab kis ntawm tib neeg, thiab tiv thaiv cov tshuaj tiv thaiv, T cell-driven tiv thaiv, thiab innat, tiv thaiv. Cov kev hloov pauv uas yuav tsum tau ua, raws li peb tau tham thoob plaws hauv Kev Tshawb Fawb no, yog qhov sib xyaw ntawm kev hloov pauv rau tus tswv tsev ntawm cov kab mob hauv lub cev thiab kev khiav tawm ntawm lub cev lossis kev tiv thaiv kab mob (Box 3). Qhov kev xav zoo tshaj plaws yog qhov txawv txav los ntawm cov kab mob ntev hauv cov neeg uas muaj kev tiv thaiv kab mob, uas tus kab mob no tuaj yeem tsim muaj tus kab mob tsis tu ncua vim tsis muaj zog tiv thaiv kab mob 67functionothesis piav qhia txog kev hloov pauv ntawm cov kev hloov pauv sai sai pom ua ntej qhov tshwm sim ntawm cov hloov tshiab,618,18. Txawm li cas los xij, nws yuav tsum tau muab sau tseg tias yav tom ntej variants tej zaum yuav ncaj qha los ntawm yav dhau los los yog tam sim no VOCs, feem ntau tsis ntev los no ua piv txwv los ntawm spate ntawm 'thib ob tiam' Omicron variants muab los ntawm BA.2, xws li BA.2.75, BJ.1, thiab BA.2., 10.4 (ref. 185). Thaum intralineage recombination ua lub sijhawm rau tus kab mob kom tau txais cov kev hloov pauv ntxiv thiab cov txiaj ntsig zoo los ntawm cov kev sib txawv ntawm qhov sib txawv, ua ntej qhov tshwm sim ntawm XBB, cov kev sib txuas ua ke tau tsuas yog cuam tshuam me me ntawm kev sib kis tam sim no (Lub thawv 2). Tsis tas li ntawd, txawm hais tias tam sim no muaj pov thawj tsawg heev rau kev tsim kom muaj kev mus sij hawm ntev thiab kev hloov pauv hauv cov tsiaj reservoir hom, xav tau kev soj ntsuam ntau thiab ua haujlwm ntawm cov kab mob raug mob vim qhov rov qab zoonosis tau raug sau tseg 4,5,186. Muaj ntau lub teb chaws uas muaj peev xwm ua tau qis los yog qhov chaw uas muaj kev soj ntsuam zoo yav dhau los uas tau txo qis los yog phasing tawm sequencing tag nrho. Qhov no yog qhov teeb meem vim tias tsis muaj kev soj ntsuam genomic yuav txhais tau tias cov kev hloov pauv yav tom ntej yuav raug kuaj pom ntau tom qab lossis tuaj yeem nthuav dav hauv qib qis ua ntej qhov tshwm sim. Yog li ntawd, muaj qhov xav tau kom nthuav dav thiab muaj kev sib txig sib luag los saib xyuas cov VOCs tshiab ntawm cov tib neeg thiab cov zej zog ua ntej lawv nthuav dav.
Cov ntaub ntawv
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