Innate Immunity, Inflamation Activation And Heat-shock Protein in COVID-19 Pathogenesis

TSAB NTAWV

SARS-CoV-2-induced COVID-19 yog ib qho kev sib kis loj ntawm lub xyoo pua 21st, uas tau ua rau muaj kev puas tsuaj loj ntawm lub neej thiab kev puas tsuaj thoob ntiaj teb. Cov tshuaj tiv thaiv zoo tiv thaiv SARS-CoV-2 tau raug ncua vim tsis muaj kev paub ntau txog nws cov txheej txheem ntawm kev ua. Nkag siab txog lub cev tsis muaj zog tiv thaiv kab mob SARS-CoV-2 thiab lub luag haujlwm ntawm heat shock proteins (HSP) hauv inhibiting thiab daws cov kab mob inflammatory yuav muab cov ntaub ntawv qhia txog tus nqi qis SARS-CoV-2 mortality rates in Africa.

Tsis tas li ntawd, cov puav puav leej yog tus tswv tsev rau cov kab mob sib txawv, suav nrog SARS-CoV-2 muaj qhov tshwj xeeb IFN-innate antiviral inflammatory teb, tsis pom muaj kab mob lossis cua daj cua dub cytokine. Peb sib tham txog txoj hauv kev molecular hauv COVID-19 nrog rau kev tsom mus rau kev tiv thaiv kab mob hauv lub cev, mob, thiab HSP cov lus teb, thiab qhia cov neeg sib tw tsim nyog rau cov hom phiaj kho mob thiab kev koom tes ntawm lub cev tiv thaiv kab mob hauv lub cev rau kev ua tau zoo ntawm mRNA lossis vector-based Corona txhaj tshuaj tiv thaiv.

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1. Taw qhia

1.1. Khau laus nas vais lav

Thawj qhov xwm txheej ntawm tus kabmob tshiab (CoV) tau tshwm sim hauv khw muag khoom noj nqaij nruab deg Huanan hauv Wuhan City/Tuam Tshoj, qhov twg qee tus neeg tau pom tias muaj mob ntsws uas tsis paub txog keeb kwm ua rau muaj mob hnyav ua pa nyuaj (SARS) (Zhu et al. ., 2019). Cov qauv ua pa los ntawm cov neeg mob no tau txheeb xyuas thiab tus neeg sawv cev etiological tau txheeb pom tias yog CoV. Tus kab mob tshiab CoV tau raug lub npe los ntawm lub koom haum saib xyuas kev noj qab haus huv hauv ntiaj teb (WHO) ua tus kab mob tshiab pneumonia infectious, "coronavirus kab mob 2019 (COVID-19) lossis COVID-SARS-CoV-2" (Novel, 2020). Zuag qhia tag nrho genomic sequence tus kheej ntawm SARS-CoV-2 tau qhia txog kev sib haum xeeb ntawm 96.2 feem pua rau COV-RATG13 pom hauv cov puav (Zhou et al., 2020b). Raws li kev txheeb cais thoob ntiaj teb, ntau dua 164.284.766 tus neeg tau kis thaum lub Kaum Ob Hlis 2019 txog Lub Tsib Hlis 2021, nrog rau cov neeg tuag ntau dua 3.406.261 tus neeg mob (https://coronavirus.jhu.edu). Kev kho mob hnyav ntawm COVID-19 tus kab mob tuaj yeem ua rau ua rau ua pa tsis ua haujlwm, tshwj xeeb tshaj yog nyob rau hauv cov neeg laus thiab cov neeg mob uas muaj cov tsos mob ua ntej xws li kub siab, ntshav qab zib mellitus, kab mob plawv, thiab kab mob ntsws ntev (Polanco li al. , 2014; Zhou et al., 2020a).

Tam sim no, tib neeg cuam tshuam los ntawm COVID-19 tuaj yeem raug kev txom nyem los ntawm kev tiv thaiv kab mob tsis zoo, ua rau muaj mob ntau dhau, hu ua cytokine cua daj cua dub (Weiss and Leibowitz, 2011) (Fig. 1). Cov mob hnyav dhau los ntawm SARS-CoV thiab Middle East Respiratory Syndrome (MERS)-CoV tau pom cov qib ntshav siab ntau ntawm ntau cov pro-inflammatory cytokines (CHIEN et al., 2006; Kim et al., 2016). Piv nrog rau cov kab mob CoV yav dhau los, COVID-19 kis tau zoo heev (Liu li al., 2020b), thiab tus nqi nce mus rau SARS tau nrawm hauv qee kis.

Txawm hais tias kev tshawb fawb tau tsom mus rau kev nkag siab txog pathophysiology ntawm COVID-19 tus kab mob, qhov tshwj xeeb molecular thiab biochemical host yam uas ua rau mob ntsws mob hnyav tseem tsis tau nkag siab zoo. Kev tshuaj xyuas rov qab ntawm cov neeg laus uas raug kev txom nyem los ntawm COVID-19 SARS tau pom tias cov kab mob kis tau siab, nce inflammatory monocytes / macrophages, neutrophil infiltration, ncua interferon (IFN) cov lus teb, thiab ntau lub cev tsis ua haujlwm, ua rau muaj kab mob hnyav (Channappanavar li al. ., 2017; Gorla et al., 2018; Matthay et al., 2019; Zhou et al., 2020a).

1.2. Kab mob

Kev kis tus kabmob tshiab tshiab SARS-CoV-2 tau ua rau muaj kev kub ntxhov thoob ntiaj teb, uas xav kom muaj kev daws teebmeem sai sai los txo qis kev hem thawj thoob ntiaj teb rau kev noj qab haus huv, kev noj qab haus huv, thiab kev lag luam.

Cov tswv yim thoob ntiaj teb tsom rau kev tswj hwm SARS-CoV-2 los ntawm kev txwv tsis pub kis tus kab mob thiab kev cuam tshuam kho mob. Raws li cov ntaub ntawv pov thawj tam sim no, nws tau pom tias SARS-CoV-2 tuaj yeem kis ntawm ib tus neeg mus rau lwm tus. Txawm li cas los xij, kev nkag siab yuav ua li cas, thaum twg, thiab ib puag ncig qhov chaw nyiam SARS-CoV-2 kev sib kis yog qhov tseem ceeb rau kev txhim kho kev tiv thaiv kab mob thiab kev tiv thaiv kev tiv thaiv. SARSCoV-2 hom kev kis tau muaj xws li xa dej, huab cua, fomite, fecal-oral, ntshav-yug, niam-rau-tus menyuam, thiab kev sib kis ntawm tsiaj mus rau tib neeg. Kev kis tus kab mob SARS-CoV-2 tuaj yeem tshwm sim los ntawm kev sib cuag ncaj qha nrog cov neeg muaj kab mob los ntawm cov qaub ncaug thiab ua pa tawm los yog lawv cov kua ua pa, uas tso tawm thaum tus neeg mob hnoos, txham, hais lus, lossis hu nkauj (Burke li al., 2020; Ghinai et al., 2020; Liu et al., 2020a). SARS-CoV-2 kev sib kis kuj tseem tuaj yeem tshwm sim los ntawm kev nthuav tawm ntawm cov xaum nuclei (aerosols) uas tseem kis tau thaum raug tshem tawm hauv huab cua nyob deb thiab sijhawm (Lub Koom Haum, 2014, 2020).

Microscopic aerosols tsim los ntawm cov neeg mob muaj peev xwm evaporate thiab tuaj yeem nqus tau thaum ua pa thiab hais lus. Yog li ntawd, tus neeg raug tsim txom tuaj yeem nqus tau aerosols thiab kis tau. Tus nqi ntawm SARS-CoV-2 nyob rau hauv aerosol txaus los ua rau kis tau rau lwm tus neeg tseem tsis tau paub. Txawm li cas los xij, kev tshawb fawb tau pom SARS-CoV-2 RNA hauv cov qauv huab cua 3 h thiab 16 teev tom qab induction ntawm aerosols (Fears et al., 2020; Van Doremalen et al., 2020). Cov kev tshawb fawb tseem pom SARS-CoV-2 RNA hauv cov qauv huab cua yam tsis muaj aerosol induction hauv chaw kho mob (Chia et al., 2020; Guo et al., 2020; Liu et al., 2020c; Santarpia et al., 2020; Zhang et al., 2020). SARS-CoV-2 RNA pom tau tias ua haujlwm tau los ntawm cov xuab moos mus rau hnub nyob rau hauv cov xwm txheej zoo (kub thiab av noo) thiab hom nto. Yog li, kev sib kis yuav tshwm sim los ntawm kev sib cuag ncaj qha nrog cov chaw hauv thaj chaw tam sim ntawd kis tus kab mob los ntawm tus neeg mob.

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Lub sijhawm tam sim no, tsis muaj ntawv tshaj tawm txog kev kis tus kabmob SARS-CoV-2 los ntawm cov quav lossis zis, tab sis tsis ntev los no, SARS-CoV-2 RNA tau kuaj pom hauv cov zis thiab quav ntawm cov neeg mob (Guan thiab al., 2020; Sun et al., 2020a; Wang et al., 2020b; Zheng et al., 2020). Tsis tas li ntawd, qee qhov kev tshawb fawb tau tshaj tawm qhov kev kuaj pom ntawm SARS-CoV-2 RNA hauv ntshav lossis ntshav, nrog rau kev rov ua dua tshiab hauv cov ntshav. Txawm li cas los xij, lub luag haujlwm ntawm kev sib kis ntawm cov ntshav tseem tsis paub meej. Tsawg tus kab mob titers hauv plasma thiab ntshav ntshav qhia tias qhov kev pheej hmoo ntawm kev sib kis los ntawm txoj kev no yuav tsawg (Le Chang li al., 2020; Wang et al., 2020b).

Spike protein (S) ntawm SARS-CoV-2 khi rau tib neeg receptor angiotensin-hloov enzyme 2 (ACE2) pib kis kab mob ntawm cov cell. ACE2 yog li ntawd tuaj yeem ua lub hom phiaj tseem ceeb rau cov tshuaj tiv thaiv kab mob nkag mus rau hauv lub hlwb (Li, 2016; Panda li al., 2020). The receptor binding domains (RBD) between SARS-CoV-1 and SARS-CoV-2 show a structural different in S protein, thiab yog li ntawd nws tsis muaj peev xwm siv cov muaj SARS-CoV{13} } vaccine for the treatment of SARS-CoV2 (Berry et al., 2004). Hauv cov neeg mob uas muaj kev pheej hmoo siab COVID-19, lub cev tiv thaiv kab mob hauv lub cev tsis tuaj yeem txo qhov mob thiab tiv thaiv cytokine cua daj cua dub (Sun et al., 2020b).

Tsab ntawv tshuaj xyuas no qhia txog kev tiv thaiv kab mob hauv lub cev, kev mob, thiab cov tshuaj tiv thaiv kab mob kub nyhiab (HSPs) cov lus teb tau qhib los ntawm SARS-CoV-2. Cov lus teb rau tus kab mob SARS-CoV-2 hauv Africa thiab cov lus qhia tau los ntawm cov puav tau tham hauv ntu thib ob ntawm qhov kev tshuaj xyuas no. Thaum kawg, peb sib tham.

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2. Innate immune response to SARS-CoV-2

Lub evolutionary conserved innate lub cev tiv thaiv kab mob yog tus tswv tsev thawj kab ntawm kev tiv thaiv kev tiv thaiv kab mob (Netea li al., 2019). Lub cev tiv thaiv kab mob hauv lub cev ua lub luag haujlwm hauv kev tshem tawm cov kab mob kis kab mob, ua rau muaj kev sib koom ua ke tiv thaiv kab mob sai sai (Catanzaro li al., 2020).

Hauv cov tsiaj yug tsiaj, microbial recognition receptors (MRRs) suav nrog Tus Xov Tooj-zoo li receptors (TLRs) thiab nucleotide-binding oligomerization domain (NOD)-zoo li receptor tsev neeg cov proteins (NLRs) tau koom nrog hauv kev tshawb nrhiav ntau yam microbes (Franchi li al. , 2008; Franchi et al., 2009b; Sansonetti, 2006). Tus qauv lees paub receptors (PRRs) sib sau ua ke ntau cov proteins los tsim ib qho kev hu ua inflammasome (Txiv neej li al., 2017), uas tuaj yeem ua rau cov txheej txheem membrane pore thiab proinflammatory cytokine overload ua rau inflammatory cell tuag hu ua pyroptosis (Nws li al., 2015; Txiv neej et al., 2017; Shi et al., 2015). Yog li ntawd, cov lus teb ntawm tus tswv tsev lub cev tiv thaiv kab mob hauv lub cev thiab cov kab mob sib kis yog lub hom phiaj kho mob hauv cov kab mob kis los ntawm kev txo qis kev mob ntau dhau thaum khaws cov tshuaj tiv thaiv kab mob.

2.1. NLRP3 inflammasome pathogenesis in SARS-CoV-2 infection

Ntawm cov qauv-kev lees paub receptors, nucleotide-binding thiab oligomerization domain (NOD)-zoo li receptors (NLRs) yog cov cytosolic receptors tshwj xeeb, uas niaj hnub saib xyuas rau cov kab mob nkag mus rau hauv cytoplasm.

NLRP3 inflammasome yog ib qho kev kawm zoo ua kom muaj mob ua paug hauv ntau tsev neeg ntawm cov kab mob. Tag Nrho NLRP3 inflammasome activation yuav tsum muaj ob txoj hauv kev qhia (Shrivastava li al., 2016). Thawj lossis thawj lub teeb liab tuaj yeem pib los ntawm TLRs thiab RIG-I-zoo li receptors (RLRs) lossis los ntawm cov protein receptor, uas ua rau muaj kev tswj hwm ntawm pro-caspase1 thiab pro-IL-1 thiab pro-IL{{ 11}} (Bauemfeind et al., 2009). Qhov thib ob lub teeb liab txoj kev ntawm NLRP3 inflammasome activation, suav nrog procaspase -1 recruitment rau NLRP3 thiab tom qab zus tau tej cov caspase paub tab -1 thiab IL-1 thiab IL-18, lub ntsiab kev nyuaj siab cuam tshuam nrog cov ntaub so ntswg puas lossis kab mob (Franchi li al., 2008). Cov txheej txheem tiav ntawm NLRP3 inflammasome activation tseem tsis tau nkag siab tag nrho.

Txawm li cas los xij, peb chav kawm sib txawv ntawm stimuli tau koom nrog hauv kev ua kom NLRP3 inflammasome: cov kab mob microbial invading thiab lawv cov khoom, suav nrog lipopolysaccharide, muramyl dipeptide, nucleic acids, thiab pore-forming toxins; cov teeb meem endogenous txaus ntshai xws li extracellular ATP, urate crystals, hyaluronan, thiab fibrillar amyloid; thiab cov crystalline ib puag ncig cov pa phem, xws li alum adjuvant, thiab ultraviolet irradiation (Baral li al., 2014; Feldmeyer li al., 2007; Franchi li al., 2009a; Schroder and Tschopp, 2010; Shaet 2014).

Raws li tau hais dhau los, SARS-CoV-2 genome encodes S proteins uas khi rau tus tswv tsev cell receptor ACE2, uas pab txhawb kev kis tus kab mob.

SARS-CoV-2 lub hnab ntawv (E) muaj me me hydrophobic protein-membrane (M) thiab nucleocapsid (N). Plaub SARS-CoV-2 cov qauv no yog qhov tseem ceeb rau kev sib sau ua ke thiab kis kab mob (Weiss and Leibowitz, 2011). Raws li tau piav qhia ua ntej, qhov pib khi ntawm SARS-CoV-2 rau lub cell cell yog pib ntawm S protein thiab ACE2 receptor (Hoffmann li al., 2020; Patel thiab Verma, 2020). SARS-CoV-2 encodes three putative ion channels (IC): protein E, ORF-3a, and ORF{14}}a (Chan et al., 2020; Ramaiah and Arumugaswami, 2020; Wu et al., 2020a). Cov tseem ceeb ntawm cov proteins E thiab ORF3a muaj (PDZ) khi motif thiab koom nrog ua rau cytokine cua daj cua dub thiab ua rau kev tuag ntawm tes ntawm lub cev tiv thaiv kab mob NLRP3 inflammasome (Nieto-Torres li al., 2015) (Fig. 2). Clinically qhov no yuav ua rau muaj zog pulmonary edema ua rau mob ua pa nyuaj siab syndrome (ARDS) (Jimenez-Guardeno ˜ li al., 2014; Nieto-Torres li al., 2014; Torres li al., 2015).

Tsis tas li ntawd, E protein ua lub luag haujlwm tseem ceeb hauv ntau qhov kev taw qhia nrog rau kev ua kom muaj kev cuam tshuam ntawm interferon regulatory factor 3 (IRF3) thiab nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB). IRF3 paub los kho kom haum xeeb rau kev tso tawm ntawm hom 1 interferon, uas ua rau kev ua haujlwm ntawm Janus kinase / signal transducers thiab activators ntawm transcription (JAK-STAT) txoj kev thiab kev qhia ntawm interferon-stimulated noob.

Ntawm qhov tod tes, E protein ua rau kev ua haujlwm ntawm NF-kB inflammatory signaling cascade thiab kev sib cuam tshuam ntawm nws cov PDZ-binding motif (PBM) nrog inflammatory yam, xws li qog necrosis factor-alpha (TNF-) thiab interleukin 6 ( IL-6) (Wang et al., 2007). Cov kev hloov no tsim cov calcium ion (Ca2 ntxiv) channel nyob rau hauv endoplasmic reticulum / Golgi apparatus intermediate compartment membrane thiab ua raws li lub zog stimuli activating cytosolic innate immune NLRP3 inflammasome. Tsis tas li ntawd, ntau lub xov tooj ntawm tes taw qhia tau pom tias ua kom NLRP3 ntawm daim nyias nyias, ua rau cov dej ntawm cov poov tshuaj (K ntxiv) lossis chloride ions (Cl− ), thiab flux ntawm Ca2 ntxiv (Di li al., 2018; Domingo-Fernandez. ´ et al., 2017; Munoz-Planillo ˜ li al., 2013; Perregaux thiab Gabel, 1994; Samways et al., 2014; Surprenant et al., 1996; Tang et al., 2017; et 1. ) as well as lysosomal disruption, mitochondrial dysfunction, metabolic change, and trans-Golgi disassembly (Swanson et al., 2019) (Fig. 2). Virallyinduced activation ntawm NLRP3 thiab downstream mediators feem ntau ua rau cov ntaub so ntswg raug mob thaum kis kab mob.

NLRP3 inflammasome sib sau ua ke thiab ua kom cov caspase-1, ua rau cov kab mob sib txuas nrog cell tuag txheej txheem pyroptosis, thiab kev loj hlob ntawm cov tseem ceeb pro-inflammatory cytokines IL-1 thiab IL18, ua rau kev txhim kho cov lus teb inflammatory ( de TorreMinguela et al., 2017). NLRP3 cleaves apoptosis-associated speck-zoo li cov protein uas muaj cov caspase recruitment domain (ASC) ntawm nws cov N-terminal pyrin domain los ntawm kev sib cuam tshuam hemophilic, uas ua rau tsim cov prion-zoo li oligomerization (Verkhratsky thiab Pelegrín, 2014). Lub xub ntiag ntawm ntau yam xws li MHC class II transcription activator (CITA), HET-E (incompatibility locus protein los ntawm Podospora anserina), thiab telomerase-associated protein nyob rau hauv nruab nrab ntawm NLRP3 inflammasome complex, muaj deoxynucleoside triphosphate (dNTPs) kev ua. uas mediates downstream oligomerization (Lu et al., 2014; Ruland, 2014; Schmidt et al., 2016). C-terminal leucine-nplua nuj rov sau npe (LRR) cuam tshuam nrog cov protein ua rau kub ntxhov (HSPs) thiab SGT1 yog suav tias yog lub luag haujlwm rau kev tswj hwm ntawm NLRP3 inflammasome kev ua si (Lo li al., 2013; Tus kav nroog li al., 2007).

Thaum NLRP3 inflammasome tau qhib, nws ua rau nws pib-cleavage ntawm procaspase-1, uas yog tus activator los kho cov txheej txheem proteolytic ntawm pro-IL-1 , pro-IL-18, thiab proapoptotic factor gasdermin D (GSDMD) (Shi li al., 2015). GSDMD txuas thiab tsim cov pore ntawm cov cell membrane, yog li yooj yim rau kev tso tawm ntawm IL-1 /IL-18 thiab ua rau pyroptosis ntxiv (He et al., 2015).

Raws li, nws pom tseeb tias SARS-CoV E protein thiab ORF-3 ua kom NLRP3 inflammasome thiab tsim kom muaj tus tswv tsev tiv thaiv kab mob (Zhao thiab Zhao, 2020). NLRP3-kev kho mob tshwm sim rau SARS-CoV-2 tej zaum yuav yog lub hom phiaj tshwj xeeb rau kev kho mob SARS-CoV2. Ambient kub, txhawb kev tsim cov tshuaj tiv thaiv tshav kub poob siab protein, tej zaum yog ib qho tseem ceeb hauv kev kho mob SARS-CoV{11}}. Kev koom tes molecular ntawm HSPs tau pom tias ua lub luag haujlwm tseem ceeb hauv kev daws teeb meem ntawm txoj kev mob ntawm tus kab mob COVID{12}} (Heck li al., 2020).

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2.2. Tus xov tooj zoo li receptors pathogenesis hauv tus kab mob SARS-CoV

Cov TLRs yog ib pab pawg ntawm innate immune receptors uas koom nrog hauv kev ua kom lub cev tiv thaiv kab mob hauv lub cev, kev tswj hwm ntawm cytokine qhia, kev ua kom tsis ncaj ntawm lub cev tiv thaiv kab mob, thiab kev paub txog cov kab mob sib txuas nrog cov qauv (PAMPs).

(Birra et al., 2020; Debnath et al., 2020; Hedayat et al., 2011). Ua ntej tus kab mob SARS-CoV-2 muaj thoob qhov txhia chaw, ntau qhov kev tshawb fawb tau pom tias TLR txoj hauv kev tseem ceeb hauv cov kab mob SARS-CoV thiab Middle East respiratory syndrome (MERS) (Birra et al., 2020). TLRs suav nrog kaum tus tswv cuab hauv tsev neeg thiab tau muab faib ua membranous thiab endosomal receptors. TLRs tau qhia nyob rau hauv ntau lub cev tiv thaiv kab mob suav nrog cov hlwb dendritic, macrophages, cov cell killer ntuj, thiab hloov lub cev tiv thaiv kab mob (T thiab B hlwb) (Angelopoulou li al., 2020). TLRs muaj ntau yam kev lees paub rau ob leeg-strand thiab ob-strand DNA kab mob.

Lub teeb liab hloov pauv ntawm TLRs suav nrog ob txoj hauv kev loj, Myeloid sib txawv thawj cov lus teb 88 (MyD88) thiab Tus Xov Tooj / interleukin -1 receptor (TIR)-domain-muaj adapter inducing interferon- (IFN- ) kuj hu ua tus xov tooj- zoo li receptor adapter molecule 1 (TRIF lossis TICAM1). Lub xub ntiag ntawm qog necrosis factor receptor-associated factor (TRAF) thiab IL-1 receptor-associated kinases (IRAK) cov proteins tuaj yeem pib ua kom qis qis ntawm cov khoom siv hluav taws xob (NF-kB) thiab Interferon regulatory factor (IRF) thiab txhuas. rau kev tsim cov hom 1 IFN thiab pro-inflammatory cytokines-interleukin-1 (IL1), IL-6, qog necrosis factor- (TNF- ), thiab IL-12. TLRs kuj tseem ua lub luag haujlwm tsis ncaj hauv lub cev tiv thaiv kab mob los ntawm kev hloov pauv qhov kev qhia ntawm co-stimulatory molecules. Kev ua haujlwm ntawm TLRs los ntawm SARSCoV-2 ua kom cov mob ua paug thiab tsim tawm ntawm IL-1 thiab IL-6. Cov kev tshawb fawb tau tshaj tawm tias qhov kev ua kom ntev ntev ntawm cov kab mob inflammasomes yog thawj qhov ua rau cov txiaj ntsig tsis zoo hauv COVID{27}} cov neeg mob (de Rivero Vaccari li al., 2020). Tsis tas li ntawd, TLRs ua rau muaj kev ua haujlwm ntawm Janus kinase transducers (JAK / STAT) ua rau macrophage activation syndrome.

Fashionably, TLRs kho tus tswv tsev xov tooj ntawm tes taw qhia txoj hauv kev thiab txo qhov kev qhia ntawm IFN receptors thiab hom 1 IFN ntau lawm, uas ua rau cov kab mob inflammatory teb (Angelopoulou li al., 2020), yog qhov tseem ceeb hauv cov kab mob CoVs. Ntau qhov kev tshawb fawb tau ua los kawm txog kev koom tes ntawm TLR cov tswv cuab. Cov kev tshawb fawb no tau pom tias TLR3 ua los ntawm TIRF txoj hauv kev los muab kev tiv thaiv kab mob SARS-CoV thiab MERS-CoV. Tus qauv TLR3 nas tau pom tias yuav qhib IRF3 thiab NF-kB txoj hauv kev, thiab kev tsim cov hom 1 IFN thiab pro-inflammatory cytokines (Birra li al., 2020).

Tsis tas li ntawd, tsis muaj kev txo qis hauv kev tso tawm ntawm cytokines tom qab kis tus kabmob coronavirus hauv TLR3 cov nas uas tawm tsam tau tshwm sim (Birra li al., 2020). TLR4 ua rau tib txoj hauv kev zoo li TLR3, tab sis TLR4 yog qhov tseem ceeb hauv cov kab mob kab mob thiab qhib los ntawm oxidized phospholipids pom nyob rau hauv feem ntau ntawm cov kab mob ntsws, kuj tau lees paub rau COVID-19.

Activated TLR4 txoj hauv kev nyob rau hauv pulmonary theem ntawm tus kab mob ua rau oxidative raug mob. TLR4 kev taw qhia txoj hauv kev ua lub luag haujlwm hauv kev ua kom muaj cov kab mob neutrophil extracellular ntxiab (NETs) thiab NET tsim hauv COVID-19 tau pom tias muaj kev mob o, uas tuaj yeem ua rau cov txiaj ntsig tsis zoo rau cov neeg mob COVID-19 (Cicco et ib., 2020). SARS-CoV-2 spike protein binds TLR1, 4, and 6, with a superior affinity for TLR4. TLR4 blockers tuaj yeem siv los ua kev kho mob rau cov neeg mob COVID{12}} (Choudhury thiab Mukherjee, 2020). Cov kev tshawb fawb tau pom tias TLR7 thiab TLR8 tau qhia ntau heev hauv lub ntsws thaum kis tus kab mob SARS-CoV thiab tuaj yeem ua lub luag haujlwm hauv cytokine cua daj cua dub hauv SARS-CoV-1 (de Groot and Bontrop, 2020). Kev tshawb fawb los ntawm tag nrho cov genomic sequencing tau qhia tias TLR7 tuaj yeem koom nrog ntau dua hauv SARS-CoV-2 pathogenesis piv rau SARS-CoV thiab MERS-CoV vim SARS-CoV-2's single-stranded RNA tuaj yeem ua ke feem ntau. rau TLR7 (Van Der Made et al., 2020). TLR7 tuaj yeem yog lwm tus neeg sib tw rau kev tsim NET hauv COVID-19 cov neeg mob, vim tias kev ua kom txoj hauv kev TLR7/8 ua rau muaj kev cuam tshuam zoo rau cov neeg mob, ua rau mob ntsws mob. Yog li ntawd, nws yuav muaj ob lub luag haujlwm hauv kev kis kab mob (MorenoEutimio li al., 2020; Veras li al., 2020).

Ntxiv mus, ob peb TLR agonists tau raug tswj xyuas kom qhib lub cev tiv thaiv kab mob hauv lub cev thiab tsim tawm ntau yam tiv thaiv hauv lub ntsws epithelial cell. Hauv qhov kev siv zog no los txo COVID-19 kev tuag, ntau qhov kev sim tshuaj ntsuam xyuas tau soj ntsuam cov txiaj ntsig ntawm cov tshuaj tiv thaiv kab mob hauv COVID-19 cov neeg mob, siv CD24Fc conjugate los thaiv kev ua kom TLR (Florindo li al., 2020). Tsis tas li ntawd, cov teebmeem antagonistic ntawm glycyrrhetinic acid tiv thaiv TLR4 muaj kev tiv thaiv kab mob hauv lub ntsws ntawm cov nas nrog mob ua pa nyuaj, yog li tiv thaiv cov ntaub so ntswg puas tsuaj (Huang li al., 2020). Nws kuj tseem tuaj yeem txhawb nqa kev ua haujlwm tiv thaiv kab mob qis qis qis qis dua ACE2 thiab kuj tseem tuaj yeem txhawb nqa kev tiv thaiv kev ua haujlwm qis qis qis qis dua ACE2. Yog li, nws tuaj yeem yog txoj hauv kev muaj peev xwm los tswj COVID-19 (Murck, 2020).

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3. HSPs-mediated CoV-2 tolerance versus immunopathology

Thaum tshav kub kub poob siab proteins (HSPs) yog intracellular proteins uas ua raws li molecular chaperones nyob rau hauv protein folding thiab protein kev lag luam ntawm intracellular compartments. Lawv raug nthuav tawm los ntawm oxidative kev nyuaj siab, noj zaub mov tsis txaus, thiab hluav taws xob.

Txawm li cas los xij, HSPs raug tso tawm rau hauv ib puag ncig extracellular los ntawm tsis yog ib qho kev paub txog txhua yam, tab sis lawv ua nrog ntau yam kev tiv thaiv kab mob hauv lub cev. Ib qho ntawm cov kev mob tshwm sim ua ntej uas muaj feem cuam tshuam nrog tus kab mob COVID-19 hnyav suav nrog cov txheeb ze tsis txaus ntawm cov lus teb rau qhov kub ntxhov (HSR) (Heck li al., 2020). Qhov tsis txaus HSR tau raug tshaj tawm tias yog qhov yuav tshwm sim hauv qab etiology rau qhov kev pom tsis zoo nyob rau hauv feem ntau cov kab mob mob ntev (Newsholme thiab de Bittencourt Jr, 2014), thiab tseem xav tias nyob hauv cov pab pawg uas muaj kev pheej hmoo siab rau COVID-19 kev tuag. (Heck thiab al., 2020).

Lub cev tiv thaiv kab mob hauv lub cev yog qhov nkag siab zoo rau stimuli thiab ceev cov hlwb hauv feeb (neutrophils) mus rau teev (monocyte / macrophages) mus rau qhov chaw raug mob. Cov lus teb sai no yog orchestrated feem ntau los ntawm kev qhia ntawm NF-kB, uas ua rau mob thaum lub sijhawm ntxov (Oeckinghaus thiab Ghosh, 2009). Cyclooxygenase-2 (COX-2) yog ib qho protein uas tsis tuaj yeem ua lub luag haujlwm rau kev tsim cov proinflammatory arachidonic acid-derived prostaglandin (PG) thiab lwm yam lipid mediators nrog rau cov tshuaj vasoactive uas ua rau kom vascular permeability thiab pab txhawb kev tuaj txog thiab ua kom cov hlwb inflammatory thiab kho cov ntaub so ntswg (Medzhitov, 2008). COX-2- muab tau los ntawm PG-E2 ua rau kub taub hau los ntawm kev thaiv cov ntaub ntawv thermosensory ntawm thaj chaw preoptic ntawm lub anterior hypothalamus, thiab thalamus, ua rau kom muaj kev sib koom tes ntawm kev sib koom siab / parasympathetic heat-sparing mechanisms, uas ua rau qhov siab ntawm cov tub ntxhais kub ( Miragem thiab Homem de Bittencourt, 2017). Qhov kub thiab txias ntawm kwv yees li 2–3 ◦C ua rau cov lus teb thaum tshav kub kub (HSR) (Singh thiab Hasday, 2013).

Cov qauv kev hloov pauv hauv cov plasma membrane suav nrog kev kis kab mob thaum lub sij hawm tsim ua npaws ua lub luag haujlwm ncaj qha hauv kev ua kom muaj cua sov 1 (HSF-1) (Anckar and Sistonen, 2011). Kev ua kom HSF-1 tswj hwm kev hloov pauv ntawm HSPs, kev qhia ntawm cytokines, thiab cov lus teb ntawm cov noob ntxov (Chen et al., 2005), suav nrog kev tswj hwm ntawm COX-2 kev hloov pauv ntawm PDE2 thaum lub sijhawm priming/action theem ntawm o (Gilroy li al., 1999). HSR tuaj yeem tshem tawm qhov mob hnyav los ntawm kev thaiv NF-kB thiab lwm yam kev mob tshwm sim hauv qab (Gilroy li al., 1999; Newsholme thiab de Bittencourt Jr, 2014; Serhan, 2011).

Kev tsim tawm ntawm HSP70 hauv kev teb rau HSF-1 kev ua kom muaj feem cuam tshuam nrog kev tsim los ntawm NF-kB thiab nws cov inhibitor (I-kB) los cuam tshuam NF-kB hloov mus rau hauv lub nucleus (Chen et al., 2005) (Daim duab . 3). Cov HSPs yog cov tshuaj tiv thaiv kab mob uas ua rau cov kab mob inflammatory (de Bittencourt Jr et al., 2007; Ianaro li al., 2003), suav nrog tom qab ua kom NLRP3 inflammasome. Kev ua kom tsis tu ncua ntawm NLRP3-dependent caspase-1- kev kho kom haum xeeb ntawm RNA-binding protein tuaj yeem txhim kho ob qho tib si kev qhia thiab kev ua haujlwm ntawm HSF-1 los txhawb HSR muaj zog (Newsholme thiab de Bittencourt Jr. , 2014; Talwar et al., 2011; Wang et al., 2013).

Kev tuag tom qab SARS-CoV-2 tus kab mob yog xav tias yog vim tus kab mob-induced elevated pro-inflammatory cytokine tso tawm, feem ntau hu ua "cytokine storm" (Huang et al., 2005; Tisoncik et al., 2012). Xwb, hauv cov neeg uas nthuav tawm HSR muaj zog tom qab kis kab mob, kev ua haujlwm tiv thaiv kab mob ntawm HSR tuaj yeem ua rau inhibition / degradation ntawm cytokines, tiv thaiv cytokine cua daj cua dub (Tanaka li al., 2014). Txawm li cas los xij, ntau yam tshuaj tsom rau txoj hauv kev tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob hauv SARS-CoV-2 cov neeg mob suav nrog chloroquine (Gao li al., 2020), hydroxychloroquine (Gautret li al., 2020), glucocorticoids (Wu et al., 2020b), xa rov qab (Wang li al., 2020a), favipiravir (Cai li al., 2020), tau sim, tsis muaj txiaj ntsig tseem ceeb tau pom.

Txawm hais tias cov txheej txheem cuam tshuam nrog ntau yam txiaj ntsig ntawm kev kho mob hyperthermic hauv cov kab mob inflammatory mob ntev tsis tau qhia meej, nws tau pom tias ua kom lub cev kub hauv tib neeg ntawm 38 thiab 39 ◦C tuaj yeem ua rau muaj kev cuam tshuam los ntawm nitric oxide ( NO)-raws li kev txhim kho ntawm endothelial muaj nuj nqi nrog rau kev mob NO-elicited HSP70 qhia (Krause li al., 2015). HSPs tuaj yeem cuam tshuam ob qho tib si NLRP3 inflammasome activation thiab caspase-1 kev ua haujlwm hauv nas macrophages (Levin li al., 2008). Yog li ntawd, lub hom phiaj nce lossis tswj lub cev kub ntawm qhov kub taub hau (38–39 ◦C) qib tuaj yeem ua kom muaj kev tiv thaiv kev ua haujlwm ntawm HSR thiab muab lwm txoj kev kho mob.

4. Constitutive heat shock response and tolerance to CoV-2

Constitutive heat shock teb yog evolutionary conserved innate stress teb system. Raws li ib txwm muaj lub cev muaj zog, nws muaj nyob rau theem qis tab sis lawv cov concentration tuaj yeem nce ntau ntxiv hauv cov lus teb rau ntau qhov stimuli xws li thermal thiab nonthermal stimuli xws li ischemia, hlau overload, oxidants, thiab kab mob (Ja¨attel ¨ a, ¨ 1993 ; Ja¨attel ¨ ¨ a and Wissing, 1992; Villar et al., 1994). Stress-induced/chronic disease-induced HSP accumululation yog suav hais tias yog ib qho kev tiv thaiv zoo heev (Bakthisaran li al., 2015; Zhang et al., 1999). Qhov kub thiab txias nyob rau hauv sub-Saharan Africa tuaj yeem yog lub zog muaj zog ntawm HSR thiab tuaj yeem ua lub luag haujlwm tseem ceeb tiv thaiv SARS-CoV-2

Tus kab mob SARS-CoV kis thoob plaws hauv cov tebchaws African tab tom poob qhov kev xav ntawm Chad Wells thiab cov npoj yaig (Wells li al., 2020) uas tau kwv yees tag nrho cov neeg tuag ntawm kwv yees li 300,000 hauv Democratic Republic of Congo ib leeg. Txawm li cas los xij, lawv qhov kev kwv yees tau raug pov thawj tsis raug vim tias tsis tshua paub txog qhov muaj zog ntawm SARS-CoV-2 hauv African lub teb chaws, suav nrog nws cov kab mob sib kis thiab qhov feem pua ntawm cov neeg kis tus kab mob uas tsim cov tsos mob, thiab cov lus teb ntawm lawv lub cev tiv thaiv kab mob. Peb paub txog qhov tsis muaj peev xwm ntsuas hauv Africa thiab qhov zoo ntawm cov ntaub ntawv khaws tseg, txawm li cas los xij raws li cov pov thawj tshawb fawb tom qab qhov kev tuag tsawg ntawm SARS-CoV-2 tsis muaj, peb xav tias qhov kub thiab txias nyob rau hauv sub. -Saharan African lub teb chaws tuaj yeem muaj peev xwm txhawb nqa HSR thiab lawv cov tshuaj tiv thaiv kab mob kom yaj cov kab mob los ntawm SARS-CoV{11}} kab mob.

Tsis tas li ntawd, cov xwm txheej ntawm COVID-19 tshwm sim nthuav tawm cov qauv ntawm kev sib koom ua ke hauv qhov chaw txias thiab qhuav, ib yam li yav dhau los SARS-CoV-1 (Araujo and Naimi, 2020). Raws li COVID-19 cov qauv huab cua, huab cua sov thiab txias ua rau muaj kev sib kis ntawm tus kab mob, thaum huab cua qhuav thiab huab cua sov tsis zoo (Ma li al., 2020; Sajadi li al., 2020). Txawm li cas los xij, tus qauv no tseem tsis paub meej thoob plaws sub-Saharan Africa thiab South East Asia (Araujo thiab Naimi, 2020). Kev nyab xeeb tuaj yeem pab txwv SARS-CoV2 (Araujo thiab Naimi, 2020; Bannister-Tyrrell li al., 2020; O'Reilly et al., 2020).

Kev kho kom rov zoo ntawm cov tshuaj tiv thaiv kab mob los ntawm kev kho mob hyperthermic tau raug qhia (Cohen, 2020), thiab tuaj yeem yog qhov kev xaiv kho mob zoo rau kev kho tus kab mob autoimmune uas tsis muaj kev koom tes ntawm kev tiv thaiv kab mob (Tukaj thiab Kaminski, 2019). Hyperthermia-induced tshav kub kev ntxhov siab tau pom tias txo cov kab mob kis los ntawm kev cuam tshuam ncaj qha ntawm cov kab mob, kev txhawb nqa ntawm ob qho tib si hauv lub cev thiab hloov pauv hloov pauv ntawm lub cev tiv thaiv kab mob thiab ua kom cov txheej txheem tswj hwm uas cuam tshuam qhov mob, thiab kev tiv thaiv ntawm cytokine cua daj cua dub uas txwv tsis pub. ua rau cov ntaub so ntswg puas ntau (Evans li al., 2015). Kev cuam tshuam thaum tshav kub kub yog ib qho ntawm cov qauv qub tshaj plaws ntawm kev tswj hwm microbial thiab niaj hnub no tseem yog ib txoj hauv kev zoo tshaj plaws rau kev tswj thiab tshem tawm cov kab mob. Tswj qhov kub ntawm 60 ◦C rau 30 min lossis 65 ◦C rau 15 feeb lossis 80 ◦C rau 1 min tau pom tias txo qis tus kabmob coronavirus tsawg kawg yog 4 npaug (Cohen, 2020). Txawm li cas los xij, kev kho qhov kub thiab txias, av noo, thiab lub sijhawm yuav tsum tau txiav tawm SAR-CoV-2 hauv vivo tseem tsis tau txiav txim siab.

Cov ntaub ntawv pov thawj kabmob kis tau qhia tias kev da dej ntau zaus tuaj yeem txo qhov kev pheej hmoo ntawm mob ntsws (Kunutsor li al., 2017a), thiab txo qis qhov tshwm sim ntawm tus kab mob ua pa (Ernst li al., 1990; Kunutsor li al., 2017b). Tsis tas li ntawd, nqus cov cua sov thiab cov av noo siab tshaj 43 ◦C rau 30 feeb tuaj yeem txo cov kab mob thiab txo cov tsos mob ntawm tus mob khaub thuas (Tyrrell li al., 1989). Kev nqus cua kub yog qhov tseem ceeb rau lub cev tiv thaiv kab mob thawj kab ntawm kev tiv thaiv los ntawm kev cuam tshuam ncaj qha lossis kev ua kom tsis muaj zog ntawm virions hauv ethmoidal sinus qhov twg lawv thawj lodge (Conti li al., 1999).

Daim ntawv thov cua sov tag nrho lub cev kuj tau raug pov thawj los txhawb lub cev tiv thaiv kab mob thib ob ntawm kev tiv thaiv nyob ntawm HSR txoj hauv kev los ntawm kev ua raws li qhov tshwm sim ntawm kub taub hau (Schieber thiab Ayres, 2016). Kev kub siab dua ntawm qhov kub taub hau tuaj yeem ua rau lub cev tiv thaiv kab mob, txhawb cov cell membrane fluidity, thiab ua kom cov cell sib txawv thiab ua kom cov kab mob antigens, ua rau cov lus teb sai rau cov kab mob virus. Kev siv hluav taws xob ncaj qha rau hauv cov hlab cua sab saud, ntawm thawj cov tsos mob ntawm tus kab mob, tuaj yeem ua haujlwm ntxiv rau inhibit lossis deactivate virions. Nyob rau hauv vitro raug cov hlwb mus rau 45 ◦C rau 20 min nkoos lub cev tiv thaiv kab mob kom tso cov HSPs txaus thiab suppresses rhinovirus multiplication los ntawm ntau tshaj 90 feem pua (Conti li al., 1999). Kev nqus cov pa nrog cov roj tseem ceeb ntxiv xws li Eucalyptus, peppermint, thiab lavender nrog cov tshuaj tiv thaiv kab mob, tuaj yeem pab ntxiv rau kev ua kom cov mucociliary tshem tawm thiab txo cov kab mob hauv lub cev nrog rau kev pab lub cev thiab lub hlwb. Qhov kev xav no yuav tsum tau rov ntsuas dua thiab ceev faj thaum lub sijhawm kho SARS-CoV-2 cov neeg mob.

Tam sim no, tsis muaj kev tshawb fawb soj ntsuam tau npaj los yog tsim los siv cov cua sov hauv kev kho mob ntawm COVID-19, tab sis cov cua sov tau siv ntev ntev hauv qhov chaw no. Cov txheej txheem kho cua sov yog xav tau los tsim cov kev tshawb fawb yav tom ntej thiab qhia txog kev kho mob kom txo qis kev pheej hmoo ntawm kev kis kab mob thaum kho nrog rau txo qis kev pheej hmoo ntawm kev kho mob xws li kub hnyiab, cramps, kiv taub hau thiab fainting, cua sov, thiab kub stroke.

Interestingly, puav nthuav qhia qhov tsis sib npaug ntawm HSP-raws li kev tiv thaiv kab mob HSR thiab tsis pom cov kab mob degenerative lossis cytokine cua daj cua dub (Ahn li al., 2019). Bat lub cev tiv thaiv kab mob txuas ntxiv ua rau NLRP3 inflammasome ua kom teb rau cov kab mob / kab mob thiab tsis muaj menyuam (Ahn li al., 2019). Tib yam tshwm sim rau cov kab mob sib txawv, suav nrog MERS tus mob coronavirus, tsis muaj kev cuam tshuam rau lawv lub peev xwm los tua kab mob (Ahn et al., 2019). Cov lus teb tsis tu ncua tau pom tias muaj feem cuam tshuam nrog HSP70-induced anti-viral interferon-gamma

(IFN- ) ntau lawm (Jacquemin li al., 2017) ntawm IFNs tswj HSP qhia, uas ntxiv txhim kho tus nqi transcription ntawm lub tshav kub poob siab noob thiab nce kev ruaj ntseg ntawm mRNA coding rau HSPs (Zhao li al., 2002). Hauv cov puav, IFN- tuaj yeem txhim kho cyPG-induced HSP70 synthesis nyob rau hauv cov kab mob kis kab mob (Pica li al., 1996), thiab IFN- -induced synthesis thiab tso tawm ntawm HSP70 mus rau lub extracellular exosomes txoj kev, uas cuam tshuam rau unaffected dendritic. hlwb (Bausero et al., 2005). HSR nyob rau hauv cov puav qhia tau hais tias muaj kev cuam tshuam sai sai ntawm cov tshuaj tiv thaiv kab mob raws li tus kab mob ER kev ntxhov siab, thiab kev daws teeb meem sai ntawm kev mob los tiv thaiv cov ntaub so ntswg puas. Txawm hais tias muaj kev sib txawv ntawm cov tsiaj, kev sib piv ntawm lub cev thiab qhov zoo sib xws ntawm cov puav 'thiab tib neeg txoj kev tiv thaiv kab mob thiab tiv thaiv kab mob uas cuam tshuam nrog HSR tuaj yeem coj qee qhov qhia txog yuav ua li cas zam lossis kho cytokine cua daj cua dub hauv COVID-19 cov neeg mob.

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5. Innate tiv thaiv kab mob rau mRNA lossis vector-based tshuaj tiv thaiv kab mob Corona

Kev siv zog los tiv thaiv cov pej xeem thoob ntiaj teb siv cov tshuaj tiv thaiv tam sim no tuaj yeem muab txoj hauv kev tawm ntawm kev sib kis thiab cov tshuaj tiv thaiv tau pom zoo thoob ntiaj teb. Lub hom phiaj ntawm cov tshuaj tiv thaiv no yog los txhawb thiab cob qhia lub cev tiv thaiv kab mob kom paub txog ib qho ntawm SARS-CoV-2 antigen, tsom rau cov protein ntau, uas tus mob coronavirus siv los npog tib neeg lub hlwb. Cov tshuaj tiv thaiv tau pom zoo tsim los ntawm Pfizer/BioNTech thiab Moderna siv mRNA thiab lipid nanoparticle (LNP) kev xa khoom thev naus laus zis, thaum cov qauv pom zoo los ntawm AstraZeneca, Johnson thiab Johnson, thiab Gam-COVID-vac (Sputnik V) muaj DNA nyob rau hauv tsis-replicating recombinant adenovirus. (AdV) vector systems (Baden et al., 2021; Logunov et al., 2021; Polack et al., 2020; Voysey et al., 2021). Ob qho tshuaj tiv thaiv los ntawm Pfizer/BioNTech (BNT162b2) thiab Moderna (mRNA1273) yog cov tshuaj tiv thaiv mRNA, qhia txog kev ua tiav ntawm 90–95 feem pua kev ua tau zoo tiv thaiv COVID-19 (Baden et al., 2021; Polack li al., 2020), Thaum cov tshuaj tiv thaiv AdV (ChAdOx1 nCoV-19) thiab Gam-COVID-vac (Sputnik V) muaj qhov nruab nrab ntawm 70 feem pua thiab 91 feem pua tiv thaiv COVID-19 (Logunov et al., 2021; Voysey et al., 2021). Me me tsuas yog paub txog cov tshuaj tiv thaiv uas txhawb lub cev tiv thaiv kab mob, kev tiv thaiv ntev, thiab yuav ua li cas txhawm rau txhim kho cov kev hloov pauv tshiab.

Txawm li cas los xij, cov tshuaj tiv thaiv tau raug tshaj tawm los ua kom tsis txhob muaj cov tshuaj tiv thaiv kab mob thiab kab mob T hlwb tom qab 2 mus rau 4 lub lis piam ntawm kev txhaj tshuaj (Sahin li al., 2020; Widge li al., 2021), thiab ua rau lub cev tsis muaj zog thiab yoog raws cov lus teb los txhawb kev tiv thaiv kab mob tsis muaj inducing. kab mob o uas yuav ua rau muaj kev phiv loj heev. Cov tshuaj tiv thaiv mRNA ua haujlwm raws li ob qho tib si immunogen (encoding tus kab mob protein) thiab adjuvant (muaj peev xwm ua kom cov lus teb Th lossis Th2). Thaum nkag ntawm ib leeg-stranded RNA (ssRNA) lossis ob-stranded RNA (dsRNA), cov no tau lees paub los ntawm ntau yam endosomal thiab cytosolic innate immune sensors. Endosomal Hu-zoo li receptors (TLR3 thiab TLR7) yog lub ntsiab TLRs uas khi dsRNA thiab txhawb kev qhia ntawm cov tshuaj inflammatory chemokines thaum cov khoom ntawm cov kab mob xws li MDA5, RIG-I, NOD2, thiab PKR khi rau ssRNA thiab dsRNA hauv cytosol ua. rau cellular activation thiab zus tau tej cov hom I interferon thiab ntau inflammatory mediators (Pardi li al., 2018).

Lub lymph node nanoparticle (LNP) cov cab kuj pab tiv thaiv mRNA rau kev nyab xeeb lub hom phiaj xa mus rau lymphatics, qhov uas nws txhawb kev txhais lus protein kom tshwm sim (Pardi li al., 2018). Ib zaug hauv LN, LNP yog engulfed los ntawm dendritic cells (DCs), uas tom qab tsim thiab nthuav tawm cov antigen rau T hlwb rau kev ua kom lub cev tiv thaiv kab mob. Cov tshuaj tiv thaiv AdV kuj tseem muaj cov khoom siv hauv lub cev, txawm hais tias cov no nyob nrog cov kab mob uas cuam tshuam rau DNA encoding lub immunogen. Tom qab txhaj tshuaj ntawm AdV, dendritic hlwb, thiab macrophages txhawb kev tiv thaiv hauv lub cev los koom nrog ntau tus qauv lees paub receptors suav nrog, TLR9-induced type I interferon secretion hauv lub ntsws muaj kab mob (Sayedahmed li al., 2020).

Txawm hais tias cov tshuaj tiv thaiv mRNA tsis khi TLR9, ob qho tshuaj tiv thaiv tau koom nrog hauv kev tsim cov hom I interferon. Dendritic hlwb thiab lwm cov hlwb uas koom nrog hauv kev tsim cov hom I interferon coj cov tshuaj tiv thaiv-derived nucleic acids encoding S protein, uas tom qab ntawd tuaj yeem txhawb nqa ob qho tib si antigenic thiab inflammatory signals kom qhib T hlwb hauv cov qog nqaij hlav txhawb kev tiv thaiv kab mob tiv thaiv SARS- CoV-2. Cov tshuaj tiv thaiv mRNA thiab AdV txhawb kev tsim cov kab mob hauv lub cev ntawm S protein thiab cov lus teb hauv lub cev, uas ua rau CD8 ntxiv thiab CD4 ntxiv rau T hlwb kom sib txawv rau hauv effector thiab nco subsets. Cov tshuaj tiv thaiv uas tau tsav los ntawm hom I interferon txhawb kev sib txawv ntawm CD4 ntxiv thiab CD8 ntxiv rau cov tshuaj tiv thaiv T hlwb tsim cov kab mob inflammatory thiab cytotoxic mediators, thiab CD4 ntxiv rau T follicular helper (TFH) hlwb, uas txhawb nqa B cell sib txawv rau hauv cov tshuaj tiv thaiv kab mob hauv cov ntshav. Cov lus teb thib ob no tuaj yeem muab kev hloov pauv rau lub sijhawm luv luv rau cov hlwb hauv lub cev xws li macrophages los ntawm qhov tshwm sim hu ua 'kev tiv thaiv kab mob' (Yao li al., 2018), thiab ua kom lub cim xeeb T hlwb thiab B hlwb los ntawm kev txhaj tshuaj thawj zaug uas ua kom muaj zog. hom I interferon, ua kom T cell nco thiab txhawb B cell sib txawv thiab muaj sia nyob, yog li qhia tias cov tshuaj tiv thaiv kab mob tuaj yeem txhawb nqa thiab txhawb lub cim xeeb ntev ntawm kev tiv thaiv kab mob.

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6. Cov lus xaus

Qhov kev tshuaj xyuas no tau sau thaum lub sijhawm; tus kab mob SARS-CoV-2 thoob ntiaj teb tau tshaj 164 lab nrog ntau dua 3 lab tus neeg tuag, nce zuj zus mus thoob ntiaj teb. Cov ntaub ntawv qub thiab tshiab hauv qhov kev tshuaj xyuas no muab kev cia siab thiab kev daws teeb meem rau kev kho tus kab mob COVID-19. Raws li kev nkag siab tam sim no, SARS-CoV-2 feem ntau kis tau los ntawm kev sib cuag thiab ua pa ua pa. Nyob rau qee qhov xwm txheej, kev sib kis hauv huab cua tuaj yeem tshwm sim hauv tsev thiab sab hauv tsev uas tsis muaj cua nkag mus rau lwm qhov.

Nws tuaj yeem xav tias TLRs muaj ob qho kev phom sij thiab muaj txiaj ntsig zoo ntawm COVID-19 kab mob. Cov ntaub ntawv qub los ntawm SARS-CoV thiab MERS tuaj yeem pab ua kom nkag siab zoo txog lub luag haujlwm ntawm cov khoom hauv lub cev thiab kev tiv thaiv kev tiv thaiv kab mob hauv COVID-19. Tsuas yog TLR7/8 paub txog ssRNA ntawm COVID-19, thaum TLR3, TLR4, thiab TLR6 tuaj yeem koom nrog COVID-19 tus kab mob. Kev siv ob qho tib si antagonists thiab agonists yuav tsum tau tshawb xyuas los txiav txim siab txog kev kho mob thiab kev phom sij ntawm TLR hauv SARS-CoV-2 kab mob. Cov theem ntawm kev kis kab mob kuj tseem ceeb rau kev txiav txim siab txog hom TLRs kev koom tes. Tsis tas li ntawd, qhov txo qis ntawm kev ua kom ntau dhau ntawm cov kab mob inflammasomes thiab NET tsim tuaj yeem yog lub hom phiaj kho mob. Thaum kawg, kev tshawb fawb txog bioinformatics tuaj yeem pab nkag siab txog kev sib cuam tshuam ntawm TLRs nrog cov proteins thiab RNA ntawm COVID-19.

Kev tshawb fawb tsis ntev los no tau pom tias, thaum muaj qee yam kab mob suav nrog SARS-CoV-2 kab mob, NLRP3 muaj peev xwm kuaj pom cov ligands, ua kom cov caspase-1, thiab ua rau muaj kev tso tawm ntau yam proinflammatory cytokines nrog lub luag haujlwm tseem ceeb tiv thaiv kab mob. (Komune et al., 2011). Qee xyoo dhau los, kev siv zog tau muab tso rau hauv kev tshawb fawb txog kev sib raug zoo ntawm tus kab mob thiab NLRP3 inflammasome. Viral RNA, viroporin, thiab cov kab mob kis kab mob ua rau NLRP3 inflammasome (Chen thiab Ichinohe, 2015). Feem ntau RNA kab mob kis tau los yog inhibits NLRP3 inflammasome los ntawm kev tswj cov ion raws thiab ROS qauv. K ntxiv efflux ua lub luag haujlwm tseem ceeb hauv NLRP3 kev ua haujlwm, txawm hais tias, Ca2 ntxiv channel thiab ROS qauv tseem muaj teeb meem.

Tam sim no, kev tshawb fawb bat tau txais kev nyiam. Ntxiv nrog rau kev ya davhlau, ntau yam kab mob lom neeg ua rau cov puav tshwj xeeb ntawm cov tsiaj. Lub cev ntawm kev tshawb fawb xws li cov ntawm Bat1K consortium147, thiab cov thev naus laus zis uas siv ib leeg-cell RNA sequencing, tso cai rau kev tsis sib haum xeeb thiab sib sib zog nqus tus cwj pwm ntawm cov puav 'cov kab mob ntawm tes thiab lawv cov haujlwm tshwj xeeb thiab txoj hauv kev. Bat host tiv thaiv lub cev tiv thaiv kab mob thiab sib npaug tus kab mob o ua rau muaj kev noj qab haus huv tshwj xeeb. Cov tswj hwm tseem ceeb thiab cov tshuab siv los ntawm puav hauv kev tswj hwm qhov sib npaug ntawm homeostatic no yog ib zaj lus qhia tseem ceeb rau kev tswj thiab tiv thaiv cov kab mob ntau yam kab mob hauv tib neeg.

Peb xav tias HSR yog txoj hauv kev tseem ceeb rau kev kho mob. Thaum kawg, peb thov kom siv HSR activators yuav tsum tau tshawb xyuas vim tias lawv tuaj yeem txo cov teeb meem COVID-19. Txawm hais tias, cov lus teb tsis tu ncua tau pom tias muaj feem cuam tshuam nrog HSP70-induced anti-viral interferon-gamma (IFN- ) ntau lawm (Jacquemin li al., 2017) ntawm IFNs tswj HSP qhia, uas ntxiv txhim kho tus nqi transcription ntawm lub tshav kub poob siab noob thiab ua kom ruaj khov ntawm mRNA coding rau HSPs (Zhao li al., 2002).

Tam sim no pom zoo cov tshuaj tiv thaiv tshiab tsim tawm los tiv thaiv SARS-CoV-2 tau ua pov thawj ua tiav, tab sis lawv cov kev tswj hwm tau cuam tshuam nrog cov tshuaj tiv thaiv autoimmune tshwm sim hauv qee pawg ntawm cov tib neeg uas xav tau. Nws tau raug pom tias cov tshuaj tiv thaiv no tsis ua rau muaj kev phom sij ntau dua li kev kis kab mob hauv lawv tus kheej, thiab cov neeg mob thiab cov kws kho mob tau txhawj xeeb txog qhov muaj feem cuam tshuam rau kev rov qab los lossis ua rau cov kab mob autoimmune zuj zus vim yog cov ntaub ntawv tsis txaus. Kev zam qhov kev pheej hmoo ntawm kev txhaj tshuaj tiv thaiv yuav tsum tsis txhob ua rau tsis kam txhaj tshuaj tiv thaiv ntxiv lawm, kev sim yuav qhia meej txog cov txheej txheem tiv thaiv kab mob ntawm cov tshuaj tiv thaiv tshiab / adjuvants hauv cov neeg no.

Cov neeg sau ntawv pab

Cov kws sau ntawv nquag pab txhawb thiab koom ua ke sau cov ntawv sau. JD thiab HS txhais cov ntsiab lus thiab cov ntaub ntawv ntawm cov ntawv sau. JD npaj cov duab.

Tshaj tawm ntawm Kev Sib Tw Kev Txaus Siab

Txhua tus kws sau ntawv tau tshuaj xyuas tsis zoo, tsis muaj kev sib tw txaus siab, thiab pom zoo rau qhov kawg version ntawm cov ntawv sau no rau kev tshaj tawm.

Kev lees paub

Peb xav ua tsaug rau Dr. Thomas Ragnar Wood rau nws lub tswv yim thaum sau tsab ntawv no.

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Cov ntaub ntawv

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