Coccidioides Immitis Thiab Posadasi; Kev Ntsuam Xyuas Ntawm Lawv Cov Kab Mob Biology, Genomics, Pathogenesis, Thiab Kev Tiv Thaiv Tus Kheej

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Coccidioides tiv thaiv kab mobthiab C. posadas yog ob hom kab mob dimorphic fungal uas muaj nyob hauv thaj chaw qhuav ntawm lub ntiaj teb tshiab, suav nrog thaj tsam ntawm sab hnub poob Texas mus rau sab qab teb thiab nruab nrab California hauv Tebchaws Meskas uas ua rau coccidioidomycosis (tseem hu ua Valley Fever). Hauv cov cheeb tsam uas muaj kab mob loj heev xws li yav qab teb Arizona, txog li 50 feem pua ​​​​ntawm cov neeg nyob ntev tau kis tus kab mob. Cov ntaub ntawv tshiab hais txog cov noob caj noob ces fungal.ecology, epidemiologY, thiab host-pathogen kev sib cuam tshuam tau dhau los ua muaj, Txawm li cas los xij, peb txoj kev nkag siab ntawm qee yam ntawm coccidioidomycosis tseem tsis tiav, suav nrog cov caj ces hloov pauv ntawm cov fungus. cov genes koom nrog hauv kev ua phem, thiab yuav ua li cas cov kev hloov pauv ntawm cov noob qhia thaum lub sij hawm lub cev lub neej dimorphic Cycle muaj feem xyuam rau kev hloov pauv los ntawm cov pwm dawb nyob rau hauv parasitic spherule. Hmoov tsis zoo, kev siv zog los tsim cov tshuaj tiv thaiv subunit muaj txiaj ntsig tseem tsis tau tsim tawm, txawm hais tias ob qho tshuaj tiv thaiv kab mob fungus tau tsim.

ARTICLE HISTORY Tau txais 13 Plaub Hlis 2018 Txais 31 Lub Xya Hli 2018

KEYWORDS Fungi; Cocidioides, cocidioidomycosis, dimorphism; kheej kheej; genome; transriptome kev tiv thaiv; tshuaj tiv thaiv

Nyem qhov no kom paub ntau ntxiv txog Cistanche

Taw qhia

Coccidiooidomycosis thawj zaug tau lees paub tias yog tus kab mob tuag taus 120 xyoo dhau los, tab sis cov fungal etiology tsuas yog txiav txim siab ob xyoo tom qab, thiab tag nrho cov kab mob digital ntawm tus kab mob tsis paub txog lwm 40 xyoo tom qab ntawd [1]. Hauv kaum xyoo dhau los, muaj kev nce qib hauv peb txoj kev nkag siab txog kev tiv thaivtiv thaiv kab mobnyob rau hauv cov nas, thiab me ntsis kev nce qib mus rau kev tsim cov tshuaj tiv thaiv. Kev nce qib hauv cov txheej txheem molecular tau siv los qhia meej txog kev sau se ntawm cov kab mob, kev kis kab mob ntawm cov cheeb tsam tseem ceeb, dimorphic, kab mob fungal endemic, thiab los sib piv cov kab mob fungal hauv nws cov morphologies sib txawv. Nws tseem yog ib qho nyuaj rau ua kom meej meej, tsom mus rau kev hloov pauv hauv cov kab mob no, uas tau txwv peb lub peev xwm los txheeb xyuas cov xwm txheej phem thiab kom nkag siab tag nrho tias cov fungus hloov pauv ntawm cov pwm mus rau hauv cov txheej txheem thiab cov kab mob tshwj xeeb (spherule) uas yog daim ntawv nws siv. hauv tus tswv tsev. Qee yam ntawm peb cov kev paub tam sim no ntawm cov teeb meem no yuav raug tham hauv qhov kev tshuaj xyuas xaiv no.

Taxonomy

Coccidioides hom yog fungi nyob rau hauv Ascomycete division, Eurotiomycetes chav kawm, thiab Onygenales xaj [2,3]. Qhov kev txiav txim no suav nrog ntau yam dimorphic tib neeg cov kab mob uas muaj peev xwm ua rau muaj kab mob sib kis hauv cov kab mob tiv thaiv kab mob, suav nrog Histoplasma capsular,Paracoccidioidesspp, thiab Blastomyces spp. Cov pwm mono-morphic, Aspergillus fumigatus, uas yog ib qho kab mob kis tau zoo, kuj pom nyob rau hauv qhov kev txiav txim no, Ntau yam tsis muaj kab mob tab sis muaj feem xyuam nrog cov tsiaj kuj pom nyob rau hauv qhov kev txiav txim no (Daim duab 1). Coccidioides thiab C. posada yog morphologically zoo tib yam thiab lawv cov proteins kwv yees yog ntau tshaj 90 feem pua ​​​​homologous [2]. Lawv tsis tuaj yeem paub qhov txawv ntawm kev kuaj serologic, tab sis ob hom tuaj yeem paub qhov txawv ntawm caj ces.polymorphisms, thiab qee qhov sib txawv ntawm cov yam ntxwv loj hlob tau raug tshaj tawm [4.5].C. posadas muaj cov pejxeem loj, uas muaj ntau haiv neeg ntau dua C. [6]. Qhov sib txawv loj tshaj ntawm ob hom yog lawv qhov chaw faib khoom. C yog feem ntau pom nyob rau hauv cov suab puam thaj tsam ntawm Central thiab Southern California (xws li Baja California), thaum C. posadas feem ntau pom nyob rau hauv cov suab puam thaj tsam ntawm Nevada, Arizona, New Mexico, West Texas, Mexico, thiab Central thiab South America implying hais tias yog. Qhov tseem ceeb thaj chaw teeb meem thaum lub sij hawm cov tsiaj sib txawv los ntawm ib tug poj koob yawm txwv [6]. Qee thaj chaw sib tshooj ntawm ob hom kuj tshwm sim hauv Southern California thiab Baja California [7]. Ob hom muaj subpopulations uas pawg hauv thaj chaw me me [8].

Daim duab 1. Ib tsob ntoo phylogenetic ntawm dimorphic fungi uas yog tib neeg cov kab mob. Ob peb cov txheeb ze uas tsis yog dimorphic thawj kab mob tau qhia rau kev sib piv (tsis tseem ceeb hauv tan). Cov kev txiav txim tau qhia rau sab xis ntawm lub thawv npe. Cov kab mob hauv txhua qhov kev txiav txim tau ntim ua ke. Cov ntaub ntawv phylogenetic tau txais los ntawm NCBI taxonomy cuab tam thiab tsob ntoo tau tsim siv Philip-3.695.

Ecology

Coccidioides sp. loj hlob nyob rau hauv arid, alkaline suab puam av nyob rau hauv California, tab sis cov av yog complex [9] thiab cov yam ntxwv ntawm cov av paug tej zaum yuav txawv ntawm endemic regions [10]. Txog tam sim no, tsis muaj ib qho txheej txheem ntawm lub cev, lom neeg, thiab tshuaj lom neeg piav qhia txhua qhov chaw uas cov kab mob tau pom, thiab txawm tias nyob rau hauv ib qho "site", cov fungus raug faib tsis sib npaug hauv cov av vim tsis paub meej. Qee cov pov thawj muaj rau qhov tseem ceeb ntawm cov carcasses ntawm cov tsiaj me me rau cov avcolonization[7], uas tuaj yeem piav qhia txog qhov rov zoo los ntawm cov qauv hauv av txawm nyob rau hauv qhov chaw uas muaj kev sib kis me me [1l], tab sis nws tsis zoo li cov tsiaj uas muaj kab mob yuav tsum tau ua kom cov av colonization [12,13].Ntxiv rau cov tsiaj carcasses hauv burrows. , zoo li muaj cov zaub mov seem uas cov tsiaj coj mus rau hauv burrows. Cov genomes ntawm Coccidioides qhia txog kev nthuav dav ntawm cov enzymes proteolytic, uas tau raug txhais ua pov thawj tsis ncaj qha tias cov fungus siv cov proteins (carcasses) raws li cov pa roj carbon monoxide nyob rau hauv nws ib puag ncig niches, raws li nws paub tias me me suab puam nas xws li kangaroo nas feem ntau muaj cov cocci. -digital granulomas hauv lawv lub ntsws [11]. Rov qab cov kab mob los ntawm cov av los ntawm kab lis kev cai tuaj yeem nyuaj [14]. Rov qab cov kab mob los ntawm nas inoculation yog qhov rhiab heev tab sis cov thev naus laus zis tseem muaj nws cov kev txwv [151. Coccidioides DNA pom nyob rau hauv tsuas yog ib feem me me ntawm cov qauv av los ntawm cov cheeb tsam nyob rau hauv Baja California thiab Arizona txawm los ntawm rhiab kev ntsuam xyuas xws li PCR [12,15], tab sis ib tug tshiab txoj kev yuav ua rau kom qhov rhiab heev thiab tshwj xeeb ntawm DNA nrhiav tau [16]. Nws tau yooj yim dua los cog C. los ntawm cov av hauv San Joaquin Valley ntawm California nyob ze rau qhov chaw uas tib neeg paub tias muaj tus kab mob [7,1ll,14]. Nthuav covkab moblos ntawm huab cua yog qhov nyuaj tshaj qhov nrhiav tau nyob rau hauv cov av txawm hais tias tsis ntev los no txoj kev loj hlob ntawm cov tswv yim tshiab yuav txhim kho qhov rhiab heev ntawm kev tshawb pom ntawm aerosolized fungal DNA [17].

Kab mob sib kis

Nws kwv yees tias 30-50 feem pua ​​​​ntawm cov neeg nyob rau hauv cov cheeb tsam uas muaj kab mob loj heev tau kis tus kab mob, raws li kuaj pom los ntawm coccidiosis ntawm daim tawv nqaij [18]. Cov kev kwv yees no yog raws li cov ntaub ntawv qub vim tias cov tshuaj ntsuam xyuas tawv nqaij tsis muaj nyob rau ntau xyoo thiab tsis muajlojKev tshawb fawb txog kab mob kis tau ua tiav txij li qhov tsis ntev los no muaj cov spherules daim tawv nqaij kuaj reagent. Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias thaj chaw muaj kev txom nyem suav nrog thaj chaw hauv nroog Phoenix, Tucson, Los Angeles, thiab San Diego, yog li ib tus tsis tas yuav mus rau qhov qhib suab puam kom cog lus coccidioidomycosis. Txawm hais tias kev loj hlob hauv nroog tej zaum yuav txo qhov kev pheej hmoo ntawm kev kis kab mob los ntawm kev txo qis ntawm thaj chaw ntawm cov av uas muaj kab mob, nws kuj ua rau cov neeg tuaj yeem muaj peev xwm kis tau los ntawm huab cua arthroconidia uas yog tsim los ntawm cov dej num uas cuam tshuam cov av, xws li kev tsim kho thiab av qeeg [19 , 20] ib. Tsis tas li ntawd, cov kab mob cua daj cua dub los ntawm thaj chaw muaj kab mob tuaj yeem kis tau rau tib neeg thiab tsiaj txhu ntau mais ntawm thaj chaw muaj xwm txheej [21].Coccidioidesyog ntsev-tiv taus kom lawv thiaj li muaj sia nyob hauv cov dej hiav txwv, thiab qhov no tuaj yeem piav qhia tias lawv tuaj yeem kis tau cov tsiaj hauv hiav txwv li cas[7,22]. Qhov xwm txheej ntawm cov neeg kis tus kab mob sib txawv me ntsis ntawm ib xyoos mus rau ib xyoos, tej zaum vim yog huab cua qauv. Lub caij ntuj no ntub dej zoo li cuam tshuam nrog cov kab mob loj dua nyob rau lub hlis tom ntej [23].Ntxiv mus, tau muaj tag nrho cov qauv mus rau cov tsos mob ntau ntxiv hauv 10 xyoo dhau los [23,24]. Txawm hais tias cov laj thawj ntawm qhov kev nce hauv qhov xwm txheej no tsis tau tsim tiav, hauv Arizona muaj cov neeg raug mob ntau dua (nrog rau cov neeg laus) tsiv ntawm thaj chaw tsis muaj kab mob mus rau thaj chaw muaj xwm txheej, uas yog ib qho kev piav qhia. Thaum cov pej xeem ntawm Central Valley ntawm California tsis nce ib yam nkaus, cov neeg mob nyob rau hauv suburban Los Angeles County tau nce ntau heev nrog rau kev nthuav dav hauv nroog [18]. Tsis tas li ntawd, ob peb lub tsev loj cuj tshiab tau tsim nyob rau hauv nruab nrab ntawm cov kab mob. thaj chaw hauv San Joaquin Valley, ua rau muaj kev tsis txaus ntseeg siab ntawm cov neeg raug kaw thiab cov neeg saib xyuas [25]. Tsis ntev los no muaj pes tsawg tus kab mob C. tau kuaj pom hauv thaj chaw qhuav nyob rau sab hnub tuaj Washington State. Cov kab mob tseem raug cais tawm los ntawm cov qauv hauv av uas kis tau tus kab mob, ntau txhiab mais sab qaum teb ntawm thaj chaw ze tshaj plaws hauv California [26]. Cov av thiab tib neeg cais tau zoo ib yam tab sis muaj caj ces txawv ntawm Central thiab Southern California cais ntawm C.

Muaj ntau qhov kev tshuaj xyuas tsis ntev los no ntawm kev kho mob tshwm sim ntawm coccidiooidomycosis uas muaj cov ncauj lus qhia ntxaws ntxaws [18,27,28].Pulmonary tsos mobyog cov laj thawj feem ntau uas cov neeg mob nrhiav kev pab kho mob, tab sis nws kwv yees tias tsuas yog 30-50 feem pua ​​​​ntawm cov kab mob yog cov tsos mob[18]. Txawm hais tias feem ntau cov kab mob tsis raug kuaj pom, feem ntau ntawm cov neeg mob ntsws ntsws nyob hauv Arizona yog vim coccidioi-domycosis [29]. Yuav luag txhua tus kab mob ntsws ntsws yog tus kheej txwv, txawm tias nyob rau hauv cov neeg mob uas muaj cov kab mob ntsws ntxiv, tab sis qee zaum, mob ntsws ntsws tuaj yeem tshwm sim rau ntau lub lis piam mus rau lub hlis [27,29].Lwm yam, tej zaum yuav muaj cov granulomas residual los yog nyias-walled kab noj hniav uas nyob twj ywm ntev tom qab tus mob ntsws tau daws.

Tsawg dua 5 feem pua ​​​​ntawm cov neeg mob immunocompetent tsim cov kab mob sib kis [21,30]. Ib cag los ntawm kev tsis yooj yim lossis kev siv tshuaj tiv thaiv kab mob, kev pheej hmoo ntawm cov kab mob sib kis tau cuam tshuam los ntawm tus tswv tsev, xws li peb lub hlis twg ntawm cev xeeb tub thiab hnub nyoog laus [30,31]. Haiv neeg kuj yog ib qho kev pheej hmoo loj rau kev tshaj tawm. Hauv ntau cov kev tshawb fawb, cov neeg uas piav txog lawv tus kheej li African-Asmeskas yog 2-10 lub sij hawm yuav tsim cov kab mob sib kis ntau dua li cov neeg nyob sab Europe qhovntsej thiaj tsis mob, txawm tias tsis muaj qhov sib txawv ntawm lawv qhov tshwm sim (xws li tshwm sim hauv tsev loj cuj thiab rau tub rog puag) [18,25.32]. Cov neeg Filipinos kuj tseem muaj feem yuav kis tau tus kab mob [33]. Cov noob thiab cov txheej txheem tom qab haiv neeg predisposition rau kev tshaj tawm tsis tau tsim.

Genomes

Cov DNA ib ntus ntawm ntau qhov kev cais ntawm C.immitis thiab ntau C. posadas cais tau raug txiav txim [8,34]. Muaj qee yamhybridizationnruab nrab ntawm ob hom [6,35]. Sequencing ntawm ib tug loj tus naj npawb ntawm kev soj ntsuam cais nyob rau hauv Arizona tau tsim hais tias yuav luag tag nrho cov genetic sib txawv hom ntawm C post [8]. Cov pab pawg ntawm kev cais tawm ntawm thaj chaw Tucson thiab Phoenix yog qhov sib txawv ntawm caj ces. Ib txoj kev tshawb fawb piv cov av cais tawm ntawm Phoenix rau kev cais tawm los ntawm cov neeg mob hauv tib cheeb tsam pom tau hais tias ib puag ncig kev sib cais muaj ntau hom kab mob sib txawv dua li cov chaw kho mob cais, tab sis tsis muaj pov thawj rau cov kab mob sib kis ntau ntxiv uas tuaj yeem piav qhia txog kev kis kab mob ntau ntxiv hauv thaj chaw ntawd [6,34].

Cov genomes ntawm Coccidioides spp. yog 28-29 megabases (Mb). Tsawg kawg yog plaubchromosomestau raug txheeb xyuas los ntawm contour-clamped homogeneous hluav taws xob nrhiav gel electrophoresis [36]. Cov genomes yog haploid thiab tsis muaj mating tau pom nyob rau hauv lossis nruab nrab ntawm hom, txawm hais tias cov noob coding rau mating muaj nuj nqi tam sim no [2] thiab genetic recombination tshwm sim [35]. Kwv yees li 18 feem pua ​​​​ntawm cov genome muaj cov DNA rov ua dua. Coccidioides sp. zoo nkaus li muaj qhov rov ua dua qhov kev hloov pauv los tswj kev loj hlob ntawm transposons [35]. Ob leeg DNA thiab ntev davhlau ya nyob twg rov transposons yog pom; Gypsy, uas yog ib qho zoo li retrovirus transposon uas muaj nyob rau hauv fungi, yog hom transposon ntau tshaj plaws. Transposons tau pom ntau zaus hauv thaj chaw genomic uas muaj ob peb hom kab ke thiab feem ntau pom hauv pawg [37]. Feem ntau ntawm cov transposons tau degenerated thiab tsis muaj tag nrho cov kev xav tau rau kev hloov pauv. Muaj qee qhov pov thawj tias C. transposons yog qhov nyiam tshaj plaws nrog cov noob coding rau cov protein phosphorylation. Tsis tas li ntawd, ntau C. noob flanked los ntawm ib co transposon superfamilies tau qhia tsis zoo [37]. Ntawm kev txaus siab, ib qho tshiab FDA-tsim PCR kev ntsuam xyuas rau kev txheeb xyuas cov kab mob hauvkuaj cov qauvthiab ib qho kev hloov tshiab ntawm qhov kev ntsuam xyuas uas yog ob qho tib si rhiab thiab tshwj xeeb rau kev siv rau hauv cov qauv hauv av cov phiaj xwm kev soj ntsuam lub hom phiaj ntawm Copia-zoo li retro-transposon uas muaj nyob rau hauv cov ntawv luam siab hauv genome [16].

Gene tsev neeg coding rau phosphotransferase kev ua ub no, protein kinases, thiab proteinases, suav nrog subtilases thiab keratinases, tau nthuav dav hauv Coccidioides spp. piv rau cov tsiaj uas ze ze [3]. Qhov no qhia tias Coccidioides spp. tej zaum tshwj xeeb rau kev loj hlob ntawm cov protein ntxiv rau cov carbohydrates. Muaj yuav luag 800 genes uas tshwj xeeb rau Coccidioides spp. thiab qee qhov nyiam tshaj tawm hauv spherules (saib hauv qab).

Dimorphism

Tag nrho cov thawj cov kab mob fungal tsuas yog Cryptococcus spp. qhia cov yam ntxwv ntawm kev ua thermally dimorphic, loj hlob raws li pwm nyob rau hauv cov av thiab sib txawv rau cov poov xab los yog spherule nyob rau hauv cov tsiaj. Coccidioides sp. loj hlob li mycelia (pwm) nyob rau hauv cov av thiab tsim spores hu ua arthroconidia nyob rau hauv lub mycelium thaum lawv loj hlob (Daim duab 2).Arthroconidiaraug tso tawm thaum cov av tsis huv raug cuam tshuam thiab txhua tus muaj peev xwm tsim tau ib qho mycelium tshiab yog tias nws tsaws hauv av, lossis ib lub spherule yog tias nws kis tau cov tsiaj txhu. Lub peev xwm los tsim spherules los ntawm arthroconidia yog xav tau rau pathogenicity. Arthroconidia puag ncig thiab ua tsis paub qab hau los ntawm isotropic kev loj hlob. Kev loj hlob ntawm spherules cuam tshuam nrog ncig ncig ntawm lub cev thiab kev faib ua ke ntawm nuclei thiab cytoplasm kom nws thiaj li ua rau lub spheruule nrog ntau pua 2-4 micron endospores. Thaum lub spherule paub tab ruptures cov endospores raug tso tawm thiab txhua tus ntawm lawv muaj peev xwm tsim tau lwm tus kheej kheej. Qhov sib txawv ntawm endospore rau hauv cov spherules paub tab yuav siv li ntawm 4-6 hnub hauv vivo yog li tus naj npawb ntawm spherules tuaj yeem nce sai heev. Kev hloov pauv ntawm arthro-conidia mus rau spherules thaum loj hlob hauv qhov nruab nrab uas tau hais tseg yuav tsum muaj qhov kub thiab txias ntawm 25 degree mus rau 37 degree, thiab nce hauv atmospheric CO, mus rau 10-14 feem pua ​​[38]. Nws tau xav tias cov xwm txheej zoo sib xws ua rau kev loj hlob spherule hauv vivo, tab sis kuj tseem muaj pov thawj tias kev sib cuag nrog neutrophils tuaj yeem txhawb nqa arthroconidia mus rau kev hloov pauv ntawm lub cev (39]. mus rau hyphal cov ntaub ntawv uas muaj o uas tshwm sim ua abortive sim ua spherules [40].

Daim duab 2. Mvcelia uas muaj arthroconidia thiab ib tug loj spherule nrog endospores, (a) mature mycelia zus nyob rau hauv vitro qhia tsaus nti stained arthroconidia alternating nrog ib tug nucleate nyias-walled ntu nyob rau hauv mycelia (lactophenol paj rwb xiav stain). (b) Ib lub spherule uas muaj cov endospores hauv cov ntaub so ntswg (Periodic Acid Schiff (PAS)).

Tsawg tsawg tsis paub txog qhov kev hloov pauv hauv cov kev pabcuam transcriptional uas kho qhov kev hloov pauv ntawm arthroconidia mus rau spherules. Tsuas muaj ob qhov kev tshawb fawb luam tawm piv cov ntawv sau ntawm mycelia rau cov spherules loj hlob hauv vitro; ib qho kawm C. thiab C. posadas siv RNA-seq thiab lwm qhov kawm tsuas yog C., siv tag nrho-genome qhib nyeem ncej microarray [41,42]. CovRNA-sibtxoj kev tshawb fawb piv rau mycelia thiab hnub 4 spherules thiab tsom rau cov noob uas tau qhia txawv ntawm ob hom. 13 feem pua ​​​​ntawm cov noob tau tswj hwm ntau dua li ob zaug hauv cov spherules ntawm ob hom, suav nrog chitin-associated proteins, -(1,3) glucan synthase, thiab spherule sab nrauv phab ntsa glycoprotein. Txoj kev tshawb nrhiav microarray piv rau C. immitis mycelia rau hnub 2 (thaum ntxov ntawm kev hloov pauv) thiab hnub 8 (endo sporulating) spherules. Cov theem ntawm kev qhia ntawm 22 feem pua ​​​​ntawm cov noob yog nce-lossis-tswj tswj ntau tshaj li ob zaug hauv hnub 2 lossis hnub 8 spherules piv rau mycelia. Kuj tseem muaj qhov sib txawv tseem ceeb ntawm cov ntawv sau tseg ntawm hnub 2 thiab hnub 8 spherules (Daim duab 3). Oxidoreductases (xws li extracellular superoxide dismutase uas tuaj yeem pab tiv thaiv kev tua neutrophil) yog tswj hwm nyob rau hnub 2 spherules, xws li cov piam thaj thauj, thioesterase, thiab amylase. Kwv yees li ib feem peb ntawm cov noob uas tau tswj hwm hauv vivo tsis muaj kev ua haujlwm thiab 5 feem pua ​​​​tsuas yog pom hauv Coccidioides spp [42]. Ib qho ntawm cov tsev neeg muaj txiaj ntsig zoo tshaj plaws uas tau tswj hwm hauv C. immitis spherules yog tsev neeg cov protein kinase; 28 ntawm 184 kwv yees cov noob protein kinase tau txo qis. Qee qhov kev tswj hwm cov protein kinase genes code rau lub voj voog ntawm tes, phab ntsa ntawm tes, thiab kev ntxhov siab cuam tshuam txog cov proteins. Qhov kev sib raug zoo ntawm cov kev cai qis ntawm cov noob no thiab kev tsim cov spherule tsis meej.

Daim duab 3. Tus naj npawb ntawm cov noob upregulated nyob rau hauv spherules ntawm peb sib txawv maturities. Venn daim duab ntawm C. immitis genes up-regulated ntau tshaj 2-fold piv rau mycelial noob qhia. (a) Cov ntaub ntawv rau hnub 4 spherules yog los ntawm [41] thiab (b) cov ntaub ntawv rau Hnub 2 thiab hnub 8 spherules yog los ntawm [42].

Ib qho ntawm cov noob caj noob ces pom nyob rau hauv ob txoj kev tshawb fawb yog 4-hydro phenylpyruvate dioxygenase (4-HPPD, los yog PDA). Cov enzyme no yog ib feem ntawm cov noob caj noob ces koom nrog hauv tyrosine catabolism. 4-HPPD degrades 4-hydroxyphenylpyruvate homogentisate, uas yog tshuaj lom. Homogentisate yog ntxiv catabolized lossis oxidized thiab polymerized los ua pheomelanin [43]. 4-HPPD tau pom tias muaj kev tswj hwm nyob rau theem poov xab ntawm tag nrho cov dimorphic thawj kab mob fungi [44]. Kev cuam tshuam ntawm 4-HPPD noob hauv Talaromyces mar-yeej tsis ua rau cov mutant uas tsis tuaj yeem loj hlob thiab sib txawv rau hauv cov poov xab hauv macrophages [45]. Cov kws sau ntawv ntawm txoj kev tshawb fawb no ntseeg tias qhov phenotype no tsis zoo li cuam tshuam ncaj qha rau cov txiaj ntsig ntawm 4-HPPD ntawm tyrosine metabolism vim tias lwm yam kev hloov pauv hauv txoj kev tyrosine catabolism tsis muaj qhov phenotype li ntawd lawv hais tias 4- HPPD tej zaum yuav muaj lwm yam khoom tsis tau pom dua.

Txawm hais tias muaj qhov sib txawv ntawm kev sim tsim thiab kev tshuaj xyuas cov ntaub ntawv, muaj 152 cov noob uas tau tswj hwm hauv cov spherules hauv ob qho kev tshawb fawb, tsis hais txog theem ntawm kev loj hlob (Daim duab 3). Ntau yam ntawm cov noob caj noob ces no muaj nyob rau hauv txoj hauv kev enzymatic ntawm complex carbohydrate metabolism (Table 1). Kev ua kom muaj txiaj ntsig ntawm cov noob hauv txoj hauv kev nyuaj carbohydrate zoo li plausible txij li kev hloov kho thiab kev sib txuas ntawm cov phab ntsa tshiab ntawm tes yuav tsum tau xav kom hloov mus rau hauv thiab kev loj hlob ntawm spherules thiab endospores. Nees nkaum rau ntawm cov noob caj noob ces tau tswj nyob rau hauv spherules kuj tau nce-tswj nyob rau hauv tus txheej txheem ntawmHistoplasmacapsulatum sib txawv rau hauv poov xab [46]. Ntxiv rau 4-HPPD, cov no suav nrog ntau tus neeg thauj khoom qab zib, tus neeg thauj khoom sulfite, amylase, keto-reductases, protein kinase, thiab polyketide synthase gene. Tsis muaj cov ntaub ntawv luam tawm cov kev tshawb fawb ntawm Coccidioides spherules hauv vivo. Proteomics yog lwm txoj hauv kev uas tuaj yeem txheeb xyuas cov noob hauv cov spherules thiab siv tau qhov hu ua hypothetical proteins. Muaj ib txoj kev tshawb fawb luam tawm siv txoj hauv kev no uas txheeb xyuas cov proteins hauv C.posa-dashi mycelia thiab spherules [47]. Lawv kuaj pom 837 cov proteins (8 feem pua ​​​​ntawm tag nrho cov kwv yees los ntawm DNA ib ntus), 88 feem pua ​​​​ntawm cov protein tau kwv yees los ntawm kev tshuaj ntsuam genome. Lawv kuj tau txheeb xyuas 172 cov proteins tshiab, feem ntau tuaj yeem raug ntaus nqi rau qhov sib txawv ntawm cov noob. Ib qho transposon protein tau qhia, qhia tias tsawg kawg yog ib qho transposon tseem ua haujlwm. Cov kev tshawb fawb zoo li no yuav ua rau kev txhim kho cov lus piav qhia ntawm genome.

Thaum cov ntaub ntawv transcriptomic no tuaj yeem txheeb xyuas cov noob uas nyiam tshaj tawm hauv spherules, lawv tsis qhia peb tias cov noob twg tsim nyog rau arthroconidia kom sib txawv rau hauv spherules thiab qhov kev hloov pauv hauv kev qhia yog qhov tshwm sim ntawm kev hloov pauv [46]. Txoj hauv kev zoo tshaj plaws los txheeb xyuas cov noob tseem ceeb rau kev tsim spherule yog txhawm rau tshem tawm lossis txo qis-tswj lawv cov lus qhia nrog kev tswj hwm RNA thiab saib xyuas cov phenotype.

Tsuas yog ob peb qhov kev tshem tawm mutants tau ua vim qhov nyuaj ntawm kev ua cov hom phiaj hloov pauv. Chitinase 2 thiab 3 noob tau qhia nyob rau theem siab dua hauv spherules dua li hauv mycelia, thiab lawv tau xav tias yog qhov tseem ceeb rau kev kho cov phab ntsa ntawm tes ntawm kev loj hlob spherules [48]. Qhov thib ob knockout ntawm cov noob no ua rau ib tug mutant uas tsis tsim mature spherules nrog endospores thiab yog avirulent nyob rau hauv nas. Qhov no mutant yog ib qho tshuaj tiv thaiv nyob rau hauv cov nas. CPSI noob kuj tseem ceeb heev rau kev ua phem vim kev tshem tawm cov noob ua rau cov spherules uas loj hlob qeeb dua li hom tsiaj qus, tsis tuaj yeem ua rau cov sporulate, thiab cov mutant yog avirulent txawm nyob rau hauv cov nas uas muaj kev tiv thaiv kab mob siab heev [49]. CPSI cov khoom lag luam tsis zoo. Cov noob tau raug xaiv los ua lub hom phiaj vim tias nws homolog yog txuam nrog cov kab mob hauv Cochiobolus hetero strophes. Nyob rau hauv mutant spherules, 33 noob tau nce lossis nqis-tswj piv rau cov tsiaj qus spherules [49]. Nws yog ib qho nyuaj rau kev txiav txim siab txog kev ua haujlwm ntawm CPSI los ntawm kev nce-thiab qis-tswj cov noob, Cov mutant no kuj yog ib qho tshuaj tiv thaiv nyob hauv cov nas. Kev tshem tawm ntawm cov noob coding rau ib lub voj voog sab nrauv glycoprotein kuj txo qis kev ua phem [50]. Sab nrauv phab ntsa glycoprotein yog tsim tshwj xeeb hauv spherules thiab tsim cov txheej txheej sab nraud uas tuaj yeem sib cuag nrog cov tswv tsev. Qhov no proline-nplua nuj proteins kuj yog ib qho adhesin uas paub los khi rau laminin.

Enzymes koom nrog hauv ammonia metabolism kuj tseem ceeb rau kev ua phem. Cov ntaub so ntswg kab mob hauv cov nas yog cov alkaline heev thiab Coccidioides synthesizes ob lub urease enzyme thiab ureido glycolate hydrolase, ib qho enzyme uas degrades ureido glycolate rau ammonia thiab glyoxylate (UGH). Ib qho urease thiab UGH ob zaug knockout mutant tsim cov ammonia tsawg dua thiab muaj kev cuam tshuam ntau heev txawm nyob hauv cov kab mob BALB / c nas, tawm tswv yim tias muaj peev xwm ua rau alkalinize lawv ib puag ncig yog qhov tseem ceeb rau cov kab mob [51]. Txawm li cas los xij, vim tias glyoxylate shunt kuj yog ib txoj hauv kev hauv cov kab mob fungi rau lub zog tsim thaum tsis muaj qabzib, UGH kev hloov pauv yuav muaj kev cuam tshuam tsis zoo dua li txo qis ammonia.

Immunology

Muaj kev sib raug zoo ntawm hom kev tiv thaiv kab mob uas tib neeg ua thiab qhov kev tshwm sim ntawm tus mob pulmonary coccidioidomycosis. Feem coob ntawm cov tib neeg muaj tus kheej txwv tsis pub muaj kab mob ntsws, thiab lawv txhim kho qeeb-hom hypersensitivity (DTH) raws li ntsuas los ntawm kev kuaj tawv nqaij zoo rau coccidiosis lossis sphere-in, tab sis lawv tsuas yog qis qis ntawm kev kho ntxiv (CF) cov tshuaj tiv thaiv. Hauv qhov sib piv, cov neeg mob uas mus tshaj tawm cov kab mob ua rau siab titers ntawm CF cov tshuaj tiv thaiv thiab tsis tsim DTH [30,52]. Txawm hais tias qhov no tau paub ntau xyoo lawm, tsis muaj kev nkag siab me ntsis lossis tsis nkag siab txog dab tsi ua rau lub cev tiv thaiv kab mob mus rau TH1 (DTH, IFNy) txoj hauv kev hauv cov neeg uas ua tau zoo. Kom meej meej, CD4 T hlwb yuav tsum tau vim cov neeg mob uas tsis tshua muaj CD4 suav vim tias tsis kho AIDS yog qhov muaj feem pheej hmoo rau kev kis kab mob [53] Cov neeg mob kho cov qog necrosis factor inhibitors kuj muaj kev pheej hmoo siab dua [54]. Peb kuj paub los ntawm cov tib neeg tsis tshua muaj kev hloov pauv caj ces uas tsis muaj peev xwm ua lossis teb rau IFNy yog qhov pheej hmoo rau kev kis tus kabmob [55,56]. Kev nce ntawm kev hloov pauv hauv lub xeev kuj tseem ua rau muaj kev cuam tshuam rau coccidioidomycosis thiab histoplasmosis, tab sis cov txheej txheem tom qab no nce kev cuam tshuam rau invasive dimorphic fungi tsis meej [57].

Kev tiv thaiv kab mob tiv thaiv kab mob thiab kev txhaj tshuaj tiv thaiv tau kawm ntau yam hauv cov nas. Nws feem ntau lees paub tias qhov kev tiv thaiv kab mob hauv lub cev txiav txim siab qhov xwm txheej ntawm lub cev tiv thaiv kab mob, thiab qhov ntawd kuj muaj tseeb hauv kev sim coccidioidomycosis. DBA/2, tus nas muaj zog tiv thaiv kab mob ua rau ntau dua IL-12p70, L-23p19, IFNy, Xeev, thiab IL-17a thiab tsawg dua IL-10 tom qab sib piv rau cov kab mob uas raug mob hnyav heev, ob qho tib si hauv Vivo thiab hauv vitro[58,59].Nyob rau hauv cov nas, nce IL-10 ntau lawm ua rau muaj kev cuam tshuam ntau ntxiv, thiab qhov sib txawv, IL-10 KO nas yog cov resistant ntau dua li qhov raug. niam txiv lim hiam, zoo ib yam li DBA/2, feem ntau resistant inbred hom [60]. Tsuas yog tus neeg tsav tsheb paub txog qhov sib txawv ntawm cov nas yog Dectin -1, glucan receptor, uas tau qhia ntawm dendritic thiab lwm cov hlwb myeloid [6]. Muaj qhov sib txawv ntawm cov qauv thiab kev ua haujlwm ntawm Dectin-1 hauv cov nas uas muaj kab mob B6 thiab resistant DBA/2 nas uas yog raws li lwm txoj kev sib txuas ntawm cov noob encoding, ClecZa [59]. Cov noob ntawd kuj tau hloov pauv hauv tib neeg lub hlwb [62,63], tab sis tsis muaj kev tshawb fawb txog qhov sib txawv ntawm qhov sib txawv cuam tshuam rau tib neeg cov lus teb rau spherules.

Nws zoo li Dectin -1 kuj yog qhov tsawg kawg yog ib feem ntawm lub luag haujlwm los tsim TH17 lub cev tiv thaiv kab mob raws li spherules cuam tshuam nrog Ctype ntawm lectin receptors [59]. Kev hloov pauv ntawm IL-17 receptor impairs lub peev xwm ntawm nas los txhim kho kev tiv thaiv tom qab txhaj tshuaj tiv thaiv los ntawm cov kab mob muaj sia nyob ntawm C.posadasi[64]. Tus neeg mob uas muaj STAT-3 kev hloov pauv, uas cuam tshuam rau CD4 TH17 qhov sib txawv, tsim tus neeg mob meningitis [65,66]. Txij li thaum STAT-3 kuj tseem koom nrog ntau lwm txoj hauv kev taw qhia nws muaj peev xwm hais tias qib qis ntawm IL-17 pom nyob rau hauv cov neeg mob no yuav tsis yog ib qho kev piav qhia rau nws qhov kev raug mob.

Cov txheej txheem uas spherules thiab / lossis endospores raug tua hauv vivo kuj tsis paub tab sis yuav tsum nyob ncaj qha ntawm CD4 ntxiv rau T hlwb vim tias muaj kev sib cuam tshuam ntawm tag nrho CD4 suav thiab kev pheej hmoo ntawm kev tshaj tawm coccidiooidomycosis hauv cov neeg mob AIDS [67]. Lub effector molecules uas tua los yog inhibit qhov sib npaug ntawm cov fungus hauv vitro tsis paub. Cov neeg uas muaj tus kab mob granulomatous ntev tsis pom zoo rau cov kab mob no, thiab tsis yog cov nas uas muaj kab mob orthologous genetic defect [68], yog li NADPH oxidase tsis xav tau. Muaj qee qhov tsis paub meej txog lub luag haujlwm ntawm iNOS. Ib qho dav-spectrum NOS inhibitor tau nce qhov cuam tshuam ntawm DBA / 2 nas mus rau C. immitis [69].Qhov sib txawv, Nos2 mutant nas strain tsis muaj kev cuam tshuam ntau dua [70]. Txawm li cas los xij, qhov kev hloov pauv ntawd tau ua hauv C57BL / 6 nas, uas lawv tus kheej ua tsawg heev TSIS tau teb rau tus kab mob no [69].

Kev siv tshuaj tiv thaiv

Kev txhaj tshuaj tiv thaiv kab mob tiv thaiv coccidiooidomycosis zoo li ua tau vim tias cov tsos mob thib ob nrog Coccidioides spp. tsis tshua muaj heev (ib qho tsis tuaj yeem cais cov kab mob subclinical uas txhawb kev tiv thaiv kab mob hauv cov cheeb tsam uas muaj kab mob loj heev)[71]. Kev txhaj tshuaj tiv thaiv tau zoo yuav tsum muaj T-cell-mediated lub cev tiv thaiv kab mob nrog rau ob qho tib si thiab TH17 lub cev tiv thaiv kab mob ua lub luag haujlwm hauv kev tiv thaiv tshuaj tiv thaiv kab mob [64]. Tsis muaj pov thawj tias cov tshuaj tiv thaiv kab mob tiv thaiv rau tib neeg vim tias tsis muaj kev sib koom ua ke ntawm kev xeeb tub los yog tau txais cov tshuaj tiv thaiv kab mob hauv lub cev thiab nthuav tawm coccidioidomycosis, tab sis hauv cov qauv nas, muaj cov pov thawj tsis sib haum xeeb txog seb B hlwb puas xav tau kev txhaj tshuaj tiv thaiv kab mob [72,73 ]. Qhov zoo tshaj plaws, cov tshuaj tiv thaiv yuav tiv thaiv lossis txo qis qhov tshwm sim ntawm tus kab mob, tab sis ib qho uas tuaj yeem tiv thaiv cov tsos mob thiab tiv thaiv cov neeg muaj kev pheej hmoo siab rau kev kis kab mob yuav raug txiav txim siab ua tiav los ntawm kev pom digital.

Cov neeg sib tw tshuaj tiv thaiv tau raug kuaj thawj zaug hauv cov nas uas muaj kab mob hauv caj ces, thiab ntau cov tshuaj tiv thaiv kab mob sib txuas tiv thaiv lawv tiv thaiv me me tab sis tsis tawm tsam loj inocula ntawm arthroconidia. Nws yog tam sim no muaj peev xwm txheeb xyuas thiab tsim cov recombinant cloned proteins uas tuaj yeem kuaj tau raws li antigens rau cov tshuaj tiv thaiv vim tias cov genomes ntawm C. immitis thiab C.posadasii muaj, thiab muaj cov gen-omes ua tiav txaus kom ib tus tuaj yeem xaiv tau. khaws cia cov proteins. Hmoov tsis zoo, tam sim no tsis muaj txoj hauv kev los twv seb qhov twg spherule proteins yuav ua rau muaj kev tiv thaiv kev tiv thaiv. Nws tau pib ntseeg tias cov proteins uas tau hais tawm ntau tshaj plaws yuav ua rau cov tshuaj tiv thaiv zoo tshaj plaws, tab sis tsis yog tag nrho cov cell-surface proteins muaj kev tiv thaiv (kev soj ntsuam tsis tau tshaj tawm, TNK). Table 2 qhia txog qee cov proteins uas rov ua dua tshiab uas tau sim ua cov tshuaj tiv thaiv [71]. Kev tiv thaiv tau raug ntsuas los ntawm kev txo qis hauv cov kab mob fungal suav los ntawm cov kab lis kev cai ntawm lub ntsws thiab tus po, thiab qee zaum los ntawm kev ciaj sia. Cov txheej txheem tseeb txawv ntawm ib qho kev kawm mus rau lwm qhov. Ib qho antigens zoo li yuav tiv thaiv me ntsis ntawm qhov zoo tshaj plaws [74-76]. Qhov ntau yam protein ntau / epitope txoj hauv kev zoo li tsim cov tshuaj tiv thaiv subunit zoo tshaj plaws[77-79]. Ib qho tshuaj tiv thaiv kab mob thib ob tau sim hauv cynomolgus macaques thiab muaj qhov txo qis ntawm tus kab mob tab sis qhov tshuaj tiv thaiv tsis tsim kom tsis muaj menyuam [79]. Txawm hais tias muaj txiaj ntsig zoo hauv cov nas thiab cov liab, kev tsim cov tshuaj tiv thaiv kab mob sib xyaw ua ke yuav tsum muaj kev txiav txim siab tseem ceeb txog cov proteins uas zoo tshaj plaws, tus nqi ntawm cov proteins, adjuvant, formulation, thiab pes tsawg koob yuav tsum tau txhaj tshuaj tiv thaiv zoo. Tej zaum qhov tseem ceeb tshaj plaws, tus kws kho mob xav tau los tsim cov khoom lag luam, muab cov neeg tsawg tsawg ntawm kev pheej hmoo kis mob. Kev npaj ua tib zoo ntawm kev sim tshuaj ntsuam xyuas kuj tseem ceeb heev. Rau tag nrho cov laj thawj no, nws yog qhov tsis muaj tseeb uas xav tias yuav muaj tshuaj tiv thaiv kom npaj rau kev tshuaj ntsuam xyuas nyob rau yav tom ntej.

Cov ntsiab lus

Kev tshawb fawb ntawm Coccidioides spp. tau ua qhov kev nce qib tseem ceeb hauv kaum xyoo dhau los. Peb txoj kev nkag siab ntawm ecology thiab pej xeem biology ntawm cov kab mob no tau txhim kho zoo heev. Qhov muaj cov kab mob genomic ntawm ntau hom kab mob tau muaj txiaj ntsig zoo rau ntau yam ntawm kev tshawb fawb, suav nrog kev tsim ntau hom kab mob uas muaj kev cuam tshuam loj heev thiab muab kev paub tseem ceeb txog kev tsim cov kab mob. Immunology ntawm coccidiooidomycosis thiab Coccidioides spp. tshuaj tiv thaiv tau nkag siab zoo dua. Hmoov tsis zoo, muaj qhov sib txawv tseem ceeb hauv peb txoj kev paub. Xav paub ntau ntxiv txog ecology ntawm cov kab mob no tseem xav tau. Nkag siab txog biology ntawm kev hloov pauv ntawm mycelium mus rau spherules yog txwv qhov zoo tshaj plaws. Xav paub ntau ntxiv txog tib neeg lub cev tiv thaiv kab mob rau tus kab mob no kuj xav tau. Txawm hais tias cloning, qhia, thiab kev sim ntawm ntau cov proteins, cov tshuaj tiv thaiv subunit tsis tau tsim. Cov no thiab lwm yam ntsiab lus muab ntau yam kev nyuaj rau yav tom ntej.