Imunopatogeneza SARS-CoV-2 infekcije – za kolege

Autori: radna grupa za kliničke i terapijske aspekte UPK

Preuzeto sa sajta

Osnovno o SARS-CoV-2 virusu

Korona virusi su familija virusa koja uzrokuje respiratorne infekcije kod čoveka i životinja. Većina članova ove famije uzrokuje lakše respiratorne infekcije, dok koronavirus teškog akutnog respiratornog sindroma (engl. severe acute respiratory syndrome coronavirus, SARS-CoV) i koronavirus bliskoistočnog respiratorninog sindroma (MERS-CoV) izazivaju teže kliničke forme bolesti koje mogu da dovedu i do akutnog respiratornog distres sindroma (ARDS). Novootkriveni član familije koronavirusa, uzrokuje koronavirusnu bolest 2019 (COVID-19), respiratornu infekciju koja može da varira od asimtomtske do teške forme.

Građa SARS-CoV-2

SARS-CoV-2 je, kao i ostali korona virusi, RNK virus čiji nukleokapsid obavija omotač. U lipidnom dvosloju omotača nalaze se površinski proteini virusa: S-protein (engl. spike) i E-protein (engl. envelope) i M-protein (engl. membrane). Od strukturnih proteina u jezgru virusa je N-protein (engl. nucleocapsid) polimerni protein koji obuhvata RNK. Sem strukturnih proteina, virusni genom kodira i 16 nestrukturnih proteina među kojima su RNK-zavisna RNK polimeraza (RdRp), enzim za replikaciju virusa, proteaza, proteini koji omogućavaju skalpanje virusa, i proteini koji ometaju funkciju interferona (IFN), antivirusnih molekula naših ćelija (1, 2).

Struktura SARS-CoV-2; Preuzeto sa sajta 

Ulazak SARS-CoV-2 u ćelije

SARS-CoV-2 u početku ulazi i replikuje se u epitelnim ćelijama gornjih respiratornih puteva (GRP) tako što se veže za angiotenzin-konvertujući enzim (ACE)-2 na površini ovih ćelija S-proteinom (3, 4). S protein se sastoji iz dva domena S1 i S2.  S-protein se za ACE2 vezuje putem RBD (engl. receptor-binding domain, RBD), koji je uokviru S1 domena, a drugi, S2 domen posreduje u fuziji virusnog omotača i ćelijske membrane. Da bi SARS-CoV-2 ušao u ćeliju, enzimi vezani za ćelijsku membranu furin i TMPRSS2 odstranjuju S1 domen, što omogućava fuziju putem S2 domena (5, 6).

Ulazak SARS-CoV- 2 u ćeliju; Preuzeto sa sajta

U odnosu na SARS-CoV ima 10-20 puta veći afinitet za ACE-2, što mu omogućava laku replikaciju u epitelu GRP, uprkos relativnoj niskoj ekspresiji ACE-2 na ćelijama te regije (7, 8). Lak ulazak u ćelije verovatno objašnjava i relativno veliki broj kopija virusa u gornjim respiratornim putevima (9), povećani nivo oslobađanja virusa (4) i značajno lakše prenošenje (10) u odnosu na SARS-CoV. SARS-CoV-2 inhibiranja i proizvodnju IFN tipa I, II i III i to više nego SARS-CoV (11, 12), što dodatno objašnjava visoke nivoe virusa u GRP, kao i visoke stope prenosa u fazi pre pojave simptoma i od strane asimptomatskih ljudi, koji mogu činiti čak polovinu svih prenosa (13).

U donjim partijama respiratornog trakta SARS-Cov-2 inficira alveolarne epitelne ćelije tipa 2, što dovodi do njihove smrti apoptozom i piroptozom (14, 15). Dodatno, SARS-CoV-2 (16-19) inficira alveolarne makrofage (AM) i dovodi do njihove aktivacije. To nije iznenađujuće, s obzirom na neposrednu blizinu ovih imunih ćelija pneumocitima tipa II i njihovu ekspresiju ACE-2 kao receptora za virus (20-22).

Aktivacija imunskih, epitelnih i endotelnih ćelija

Smrt alveolarnih epitelnih i endotelnih ćelija usled infekcije virusom dovodi do oslobađanja molekulskih obrazaca oštećenja (engl. damage-associated molecular patterns, DAMP) (23-25). DAMP-ovi oslobođeni iz mrtvih ćelija su ligandi za receptore ćelija urođene imunosti, kao što su makrofagi. Vezivanje DAMP-ova ovim receptorima dovodi do aktivacije ovih urođenih ćelija.

Aktivirani makrofagi (AM) igraju glavnu ulogu u održavanju imunološke homeostaze u plućima, suočeni s invazijom patogena i oštećenjem tkiva usled zapaljenja. Glavni mehanizmi uključuju fagocitozu umirućih ćelija, izlučivanje antiinflamatornih medijatora kao što su transformišući faktor rasta (TGF)-β, prostaglandin E2 (PGE2) i polienoične masne kiseline (PFA), i inhibicija aktivacije T-ćelija u cirkulaciji (21, 22). Međutim, jednom aktivirani, makrofagi izlučuju niz proinflamatornih citokina i hemokina, kao što su TNF, IL-1β, IL-6 i IL-8 (26-28). Pored toga, AM takođe luče mikrovezikle koji sadrže visoke nivoe TNF (29). Ovo povećanje izlučivanja medijatora zapaljenja je praćeno povećanjem broja AM polariziranih u visoko inflamatorni ili M1 fenotip, a ne antiinflamatorni tolerogeni M2 fenotip koji preovladava u fiziološkim uslovim (30, 31).

TNF i IL-1 indukuju aktivaciju endotelnih ćelija (EC) (32, 33), što dovodi do značajnog povećanja propusnosti plućnog vaskularnog endotela (34). Aktivacija EC takođe podstiče regrutaciju neutrofila iz cirkulacije kroz regulaciju hemokina površinskih membrana, ponajviše CCL5, CXCL1, MCP-1 i IL-8, proteina površinske adhezije P-selektin, VCAM-1, ICAM-1 i niz glikozaminoglikana, koji igraju bitnu ulogu u vezivanju i migraciji neutrofila (35-37).

Aktivacija trombocita i neutrofila

Trombociti u plućnoj cirkulaciji se takođe aktiviraju visokim nivoima proinflamatornih citokina i reaktivnih oblika kiseonika koji luče alveolarni makrofagi i aktivirane epitelne ćelije tipa II (38). Aktivirani trombociti (AP) i sami postaju značajan izvor proinflamatornih citokina i reaktivnih oblika kiseonika (39-41). Stvaraju se kompleksi trombocita i neutrofila koji imaju manju brzinu u poređenju sa samo trombocitima i neutrofilima, a ovo svojstvo u kombinaciji sa povećanom adhezivnošću endotela povećava sekvestraciju neutrofila i trombocita u malim krvni sudovima pluća (42-44). Pored toga, aktivirani trombociti i neutrofili međusobno pojačavanju stvaranje proinflamatornih citokina i reaktivnih oblika kiseonika (engl. reactive oxigen species, ROS) (45-49). Ovo olakšava aktivaciju neutrofila, pojačavajući njihov kapacitet za fagocitozu i oslobađanje ROS-a i drugih citotoksičnih molekula kao što je mijeloperoksidaza (50, 51). Trombociti takođe stimulišu oslobađanje neutrofilnih ekstracelularnih klopki (engl. neutrophil extracellular traps, NET) (52, 53), DNK neutrofila koja ima ulogu u fagocitozi, i sledstvenu smrt neutrofila (54-56). Zauzvrat, NET-ovi stilmulišu povećanje nivoa aktivacije trombocita, agregacije i aktivaciju trombina posredovanu tkivnim faktorom, što rezultira pojačanom intravaskularnom koagulacijom (57-59).

Vremenom, kombinovani efekti aktiviranih EC, neutrofila i trombocita i NET-ova u plućnoj alveo-kapilarnoj mreži dovode do razvoja jakog zapaljenja i prokoagulantnog stanja koje se karakteriše hiperaktivacijom kaskade koagulacije i relativnim iscrpljivanjem fibrinolitičkog sistema, s prekomernom oslobađanjem proinflamatornih citokina, DAMP-ova i taloženjem fibrina. Ovo se opisuje kao imuno-tromboza (60-62). Ovo stanje ima glavnu patofiziološku ulogu u razvoju i pogoršanju sistemske sepse jer dovodi do stvaranja mikrotromba, razvoja DIC-a i sindroma multiple organske disfunkcije (63-65).

Imuno-patofiziologija ARDS-a. Preuzeto iz (66)

Pored pluća, ACE-2 je prisutan na ćelijama mnogih tkiva: pre svega na endotelu u krvnim sudovima mnogih organa, glatkim mišićnim ćelijama zida krvnih sudova, enterocitima, epitelnim ćelijama bubrežnih tubula i podocitima, β-ćelijama pankresa (8). Smatra se da bi virus mogao da ošteti tkiva van respiratornog trakta direktno, replikacijom u ćelijama parenhima, kao i replikacijom u endotelnim ćelijama, i sledstvenim poremećajem koagulacije usled povrede endotela (67). Još uvek nije razjašnjeno kako SARS-CoV-2 dospeva u različita tkiva i koliki je udeo direktnog oštećenja u van plućnim manifestacijama COVID-19.

Aktivacija T-lifmocita

Za sve navedeno zaslužan je prevashodno odgovor urođenih imunskih ćelija. Međutim, stanje teške hronične upale i oksidativnog stresa viđeno kod pacijenata sa uznapredovalim ARDS-om može dovesti do limfopenije, ugrožene funkcije leukocita i visokog odnosa broja pomoćničkin T-limfocita Th17 prema regulatornim T ćelijama (Treg) (68-73), doprinoseći patofiziologiji stanja. Th17 ćelije takođe igraju patološku ulogu u razvoju i pogoršanju ARDS-a (74). Glavni mehanizam je povećana proizvodnja IL-17 (75-77). Ovo je visoko citotoksični molekul koji može izazvati značajne nivoe oštećenja tkiva i igra glavnu ulogu u regrutaciji neutrofila s periferije (78). Visok nivo IL-17 pokazatelj je loše prognoze kod pacijenata sa ARDS-om (78). Važnost Th17 i Treg u patofiziologiji ARDS-a naglašavaju podaci koji sugerišu da je odnos Th17: Treg prediktor 28-dnevnog mortaliteta u kod pacijenta sa ARDS-om na mehaničkoj ventilaciji (78).

Treg igraju važnu ulogu u prevenciji i razrešenju ARDS-a na nekoliko načina, kao što su podsticanje klirensa neutrofila, inhibicija efekata IL-6 i podsticanje M2 polarizacije alveolarnih makrofaga (79). Treg takođe ublažavaju nekontrolisanu upalu putem sekrecije antiinflamatornih citokina IL-10 i TGF-β koji smanjuju proizvodnju TNF i IL-1β od strane rezidentnih i infiltrirajućih makrofaga (74, 79).

Kod većine obolelih od COVID-19 se ne razvijaju dugoročne sekvele (koliko je do sada poznato) kao što je fibroza pluća, koja je prisutna u oko 26% nalaza na CT-u (78). Međutim, abnormalan nalaz na CT-u, koji varira u pogledu težine i zahvaćenosti plućnog tkiva, u infekciji SARS-CoV-2 virusom je prisutan kod visokog broja obolelih, uključujući i asimptomatske bolesnike i decu (78). Fibroza je proces koji se dešava pod kontrolom makrofaga M2 fenotipa.

Poseban problem predstavlja i dugotrajna forma bolesti  (engl. „long covid“) koja ne predstavlja posledičnu onesposobljenost usled teške bolesti, već se javlja kod obolelih sa blažom kliničkom formom (80).

Iako u oštećenju tkiva posreduju imunske ćelije, protektivan celularni i humoralni imunski odgovor je suštinski način prevazilaženja ove infekcije, s obzirom da su terapijske mogućnosti ograničene (81). Iako se ne zna egzaktno koliko traje protektivan imunitet posredovan antitelima nakon SARS-CoV-2 infekcije, razumno je pretpostaviti da je uporediv sa trajanjem imuniteta nakon infekcija srodnim virusima – bar godinu dana (82). Na mogućnost detekcije antitela na SARS-CoV-2 utiče sama dinamika humoralnog imunskog odgovora i sposobnost detekcije testa koji se koristi. Senzitivnost raznih seroloških testova varira (83, 84), ali ni uz korišćenje najosetljivijih tehnika nije moguće detektovati antitela u ranoj simptomatskoj fazi. Implikacija je da je potpuno besmisleno koristiti serološke testove kao dijagnostičko sredstvo za dokazivanje prisustva/odsustva SARS-CoV-2 infekcije pre druge nedelje od početka simptoma infekcije (85).

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