Abstract
Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human TB resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human tuberculosis disease, with a dominance of a type I IFN response and neutrophil activation and recruitment, together with a loss in B lymphocyte, NK and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B, NK and T cell effector responses in the lung upon infection. Importantly, the blood signature of active disease shared by mice and humans is also evident in latent tuberculosis progressors before diagnosis suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
Highlights
Not explain why mostindividuals controlinfection, whereas a subset go onto develop active TB
TuberculosislaboratorystrainH37Rvorclinicalisolate HN87821,22 (Supplementary Fig.1a-c;Fig.1,SupplementaryTables[1,2,3]).ThehumanbloodTBsignature[16] was firsttestedon microarraydatafrombloodofH37RvinfectedBALB/c miceatdifferent time-points post-infection,to establishthe peaktranscriptomicresponse, where immunesignatures were barely detectable at days 14 and 21 post-infection, but most significant by day 138(Supplementary Fig. 2a; Supplementary Table 3)
Analysisofblood microarraydatafromanindependentstudy30,showedthatthe bloodsignaturein129S2andC57BL/6NCrl micewasagainbarelydetectableatday 14post H37Rvinfection,beingobservedrobustlybyday[21], which wastheendpointofthatstudy[30] (SupplementaryFig.2a).Upontestingalungdisease modular signature[31] on microarray datafromlungs of H37Rvinfected BALB/c mice, we detected a peak response at day 56 post-infection, only starting to be detected by 28 days post-infection(Supplementary Fig. 2b; Supplementary Table 4). Based on these data wetestedthe human bloodtranscriptional TBsignature[16] andlung disease modularsignature31,onthebloodandlungs,respectively,from C57BL/6J and C3HeB/FeJ miceinfected with HN878, at days 26 to 56 post-infection (SupplementaryFig.3aandb;SupplementaryTables3and[4]).Thepeakresponse chosen wasca.42dayspost-infection, whichbestshowedarobustsignaturein blood and lungs from HN878 infected C57BL/6J and C3HeB/FeJ mice (SupplementaryFig.3aandb;SupplementaryTables3and4;tissuesfrom HN878 infected susceptible mice were harvested after 33-35 days postinfection dueto excessive pathology)
Summary
not explain why mostindividuals controlinfection, whereas a subset go onto develop active TB. A bloodtranscriptional signaturein active TB patients has 70 implicatedtypeIIFNin TBpathogenesis[8,9,10,11,12,13,14,15,16].Immunologicalheterogeneityinthe. A globalsystematicanalysistodetermine potential commonpathwaysofprotectionorpathogenesisindifferentTB mouse modelsand humandiseasehasnotbeenreported.ArolefortypeIIFNinTBpathogenesis8-16is supportedby mouseTB models[6,18] withelevatedandsustainedlevelsoftypeIIFN: (i)infection of particular genetic strains of mice with clinicalisolates of M. Whetheritisthegeneticstrainof mouseorthe M.tuberculosis pathogenitself whichresultsinanimmuneresponsethat most resembleshumanTBisunclear.Althoughthespectraofhuman[28] and mouse[29] TB diseasedonotcompletelyoverlap,comparisonofhumanTBwithgeneticallydiverse backgroundsof micehasestablishedpointsofsimilarityintheirresponsetoM. Tuberculosis.Increasedexpressionofgranulocyte-associatedgenesinbloodfrom active TBpatients, TB-susceptible miceandLTBI-progressorsbefore TBdiagnosis suggestedtheirroleinearlydiseasepathogenesis. Under-abundanceof B, NK and effector Tcell-signaturesin bloodfrom human TB patients[16], LTBIprogressors and TB-susceptible mice and yet over-abundanceinlungs of M. tuberculosisinfected C57BL/6Jresistant micereinforcedtheirroleinearlydisease control.Thetranslationallyrelevantknowledgedatasetpresentedhereonpotential pathwaysofprotectionandpathogenesisinhumanTBareeasilyaccessibleusing anonline ShinyApp:https://ogarra.shinyapps.io/tbtranscriptome/
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