Multimodal profiling of biostabilized human skin modules reveals a coordinated ecosystem response to injected mRNA-1273 COVID-19 vaccine.

human skin modules immune response mRNA vaccine tracking multiplexed imaging single‐cell RNA‐Seq

Journal

Allergy
ISSN: 1398-9995
Titre abrégé: Allergy
Pays: Denmark
ID NLM: 7804028

Informations de publication

Date de publication:
19 Aug 2024
Historique:
revised: 26 06 2024
received: 14 12 2023
accepted: 28 06 2024
medline: 19 8 2024
pubmed: 19 8 2024
entrez: 19 8 2024
Statut: aheadofprint

Résumé

The field of drug development is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials. Here we introduce a new flexible solution designed for the comprehensive monitoring of the natural human skin ecosystem's response to immunogenic drugs over time. Based on unique bioengineering to preserve surgical resections in a long survival state, it allows for the first time a comprehensive analysis of resident immune cells response at both organ and single-cell levels. Upon injection of the mRNA-1273 COVID-19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. The vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell-cell communications in surrounding immune cell subsets. Given its direct translational relevance, this approach provides a multiscale vision of genuine human tissue immunity that could pave the way toward the development of new vaccination and drug development strategies.

Sections du résumé

BACKGROUND BACKGROUND
The field of drug development is witnessing a remarkable surge in the development of innovative strategies. There is a need to develop technological platforms capable of generating human data prior to progressing to clinical trials.
METHODS METHODS
Here we introduce a new flexible solution designed for the comprehensive monitoring of the natural human skin ecosystem's response to immunogenic drugs over time. Based on unique bioengineering to preserve surgical resections in a long survival state, it allows for the first time a comprehensive analysis of resident immune cells response at both organ and single-cell levels.
RESULTS RESULTS
Upon injection of the mRNA-1273 COVID-19 vaccine, we characterized precise sequential molecular events triggered upon detection of the exogenous substance. The vaccine consistently targets DC/macrophages and mast cells, regardless of the administration route, while promoting specific cell-cell communications in surrounding immune cell subsets.
CONCLUSION CONCLUSIONS
Given its direct translational relevance, this approach provides a multiscale vision of genuine human tissue immunity that could pave the way toward the development of new vaccination and drug development strategies.

Identifiants

pubmed: 39157907
doi: 10.1111/all.16273
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : European Research Council
Pays : International
Organisme : Agence Nationale de la Recherche
Organisme : Genoskin

Informations de copyright

© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Références

Zhang C, Merana GR, Harris‐Tryon T, Scharschmidt TC. Skin immunity: dissecting the complex biology of our body's outer barrier. Mucosal Immunol. 2022;15:551‐561.
Kabashima K, Honda T, Ginhoux F, Egawa G. The immunological anatomy of the skin. Nat Rev Immunol. 2019;19:19‐30.
Bahl K, Senn JJ, Yuzhakov O, et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther. 2017;25:1316‐1327.
Feldman RA, Fuhr R, Smolenov I, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine. 2019;37:3326‐3334.
Thomas SJ, Moreira ED, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid‐19 vaccine through 6 months. N Engl J Med. 2021;385:1761‐1773.
Alberer M, Gnad‐Vogt U, Hong HS, et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open‐label, non‐randomised, prospective, first‐in‐human phase 1 clinical trial. Lancet. 2017;390:1511‐1520.
Liang F, Lindgren G, Lin A, et al. Efficient targeting and activation of antigen‐presenting cells in vivo after modified mRNA vaccine administration in Rhesus Macaques. Mol Ther. 2017;25:2635‐2647.
Verbeke R, Hogan MJ, Loré K, Pardi N. Innate immune mechanisms of mRNA vaccines. Immunity. 2022;55:1993‐2005.
Bergers LIJC, Reijnders CMA, van den Broek LJ, et al. Immune‐competent human skin disease models. Drug Discov Today. 2016;21:1479‐1488.
Moon S, Kim DH, Shin JU. In vitro models mimicking immune response in the skin. Yonsei Med J. 2021;62:969‐980.
Hofmann E, Schwarz A, Fink J, Kamolz LP, Kotzbeck P. Modelling the complexity of human skin in vitro. Biomedicine. 2023;11:794.
Leboux RJT, Schipper P, van Capel TMM, et al. Antigen uptake after intradermal microinjection depends on antigen nature and formulation, but not on injection depth. Front Allergy. 2021;2:642788.
Beaujean M, Uijen RF, Langereis JD, et al. The immunological effects of intradermal particle‐based vaccine delivery using a novel microinjection needle studied in a human skin explant model. Vaccine. 2023;41:2270‐2279.
Jones GB, Collins DS, Harrison MW, Thyagarajapuram NR, Wright JM. Subcutaneous drug delivery: An evolving enterprise. Sci Transl Med. 2017;9:eaaf9166.
Bittner B, Richter W, Schmidt J. Subcutaneous Administration of Biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32:425‐440.
Serhan N, Basso L, Sibilano R, et al. House dust mites activate nociceptor‐mast cell clusters to drive type 2 skin inflammation. Nat Immunol. 2019;20:1435‐1443.
Tauber M, Basso L, Martin J, et al. Landscape of mast cell populations across organs in mice and humans. J Exp Med. 2023;220:e20230570.
Qiu X, Mao Q, Tang Y, et al. Reversed graph embedding resolves complex single‐cell trajectories. Nat Methods. 2017;14:979‐982.
Rinaldi AO, Li M, Barletta E, et al. Household laundry detergents disrupt barrier integrity and induce inflammation in mouse and human skin. Allergy. 2024;79:128‐141.
Efremova M, Vento‐Tormo M, Teichmann SA, Vento‐Tormo R. CellPhoneDB: inferring cell‐cell communication from combined expression of multi‐subunit ligand‐receptor complexes. Nat Protoc. 2020;15:1484‐1506.
Pilishvili T, Gierke R, Fleming‐Dutra KE, et al. Effectiveness of mRNA Covid‐19 vaccine among U.S. health care personnel. N Engl J Med. 2021;385:e90.
Hattaway ME, Black GP, Young TM. Batch correction methods for nontarget chemical analysis data: application to a municipal wastewater collection system. Anal Bioanal Chem. 2023;415:1321‐1331.
Morelli P, Gaspari M, Gabriele C, et al. Proteomic analysis from skin swabs reveals a new set of proteins identifying skin impairment in atopic dermatitis. Exp Dermatol. 2021;30:811‐819.
Starr I, Seiffert‐Sinha K, Sinha AA, Gokcumen O. Evolutionary context of psoriatic immune skin response. Evol Med Public Health. 2021;9:474‐486.
Welss T, Sun J, Irving JA, et al. Hurpin is a selective inhibitor of lysosomal cathepsin L and protects keratinocytes from ultraviolet‐induced apoptosis. Biochemistry. 2003;42:7381‐7389.
Otsuka Saito K, Fujita F, Toriyama M, et al. Roles of TRPM4 in immune responses in keratinocytes and identification of a novel TRPM4‐activating agent. Biochem Biophys Res Commun. 2023;654:1‐9.
Chen X, Lloyd SM, Kweon J, Gamalong GM, Bao X. Epidermal progenitors suppress GRHL3‐mediated differentiation through intronic polyadenylation promoted by CPSF‐HNRNPA3 collaboration. Nat Commun. 2021;12:448.
Sun BK, Boxer LD, Ransohoff JD, et al. CALML5 is a ZNF750‐ and TINCR‐induced protein that binds stratifin to regulate epidermal differentiation. Genes Dev. 2015;29:2225‐2230.
Akinc A, Querbes W, De S, et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand‐based mechanisms. Mol Ther. 2010;18:1357‐1364.
Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12:580‐587.
van Riggelen J, Yetil A, Felsher DW. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat Rev Cancer. 2010;10:301‐309.
Bretones G, Delgado MD, León J. Myc and cell cycle control. Biochim Biophys Acta. 2015;1849:506‐516.
Dabitao D, Margolick JB, Lopez J, Bream JH. Multiplex measurement of proinflammatory cytokines in human serum: comparison of the meso scale discovery electrochemiluminescence assay and the cytometric bead array. J Immunol Methods. 2011;372:71‐77.
Cambien B, Pomeranz M, Millet MA, Rossi B, Schmid‐Alliana A. Signal transduction involved in MCP‐1‐mediated monocytic transendothelial migration. Blood. 2001;97:359‐366.
Vulcano M, Albanesi C, Stoppacciaro A, et al. Dendritic cells as a major source of macrophage‐derived chemokine/CCL22 in vitro and in vivo. Eur J Immunol. 2001;31:812‐822.
Szabo PA, Levitin HM, Miron M, et al. Single‐cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat Commun. 2019;10:4706.
Reynolds G, Vegh P, Fletcher J, et al. Developmental cell programs are co‐opted in inflammatory skin disease. Science. 2021;371:eaba6500.
Alkon N, Bauer WM, Krausgruber T, et al. Single‐cell analysis reveals innate lymphoid cell lineage infidelity in atopic dermatitis. J Allergy Clin Immunol. 2022;149:624‐639.
Schneider VA, Graves‐Lindsay T, Howe K, et al. Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly. Genome Res. 2017;27:849‐864.
Squair JW, Skinnider MA, Gautier M, Foster LJ, Courtine G. Prioritization of cell types responsive to biological perturbations in single‐cell data with augur. Nat Protoc. 2021;16:3836‐3873.
Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021;6:1078‐1094.
Stocki P, Morris NJ, Preisinger C, et al. Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA). Cell Stress Chaperones. 2010;15:729‐741.
Zhao J, Fok AHK, Fan R, et al. Specific depletion of the motor protein KIF5B leads to deficits in dendritic transport, synaptic plasticity and memory. elife. 2020;9:e53456.
Chen R, Zhang H, Wu W, et al. Antigen presentation machinery signature‐derived CALR mediates migration, polarization of macrophages in glioma and predicts immunotherapy response. Front Immunol. 2022;13:833792.
Roßmann L, Bagola K, Stephen T, et al. Distinct single‐component adjuvants steer human DC‐mediated T‐cell polarization via toll‐like receptor signaling toward a potent antiviral immune response. Proc Natl Acad Sci USA. 2021;118:e2103651118.
Schmidt ST, Khadke S, Korsholm KS, et al. The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen‐specific CD8(+) T‐cell responses: the immunological consequences of the biodistribution profile. J Control Release. 2016;239:107‐117.
Rosenbaum P, Tchitchek N, Joly C, et al. Vaccine inoculation route modulates early immunity and consequently antigen‐specific immune response. Front Immunol. 2021;12:6‐15. https://www.frontiersin.org/articles/10.3389/fimmu.2021.645210
Scholaert M, Houmadi R, Martin J, et al. 3D deconvolution of human skin immune architecture with multiplex annotated tissue imaging system. Sci Adv. 2023;9:eadf9491.
Liu X, Zhu R, Luo Y, et al. Distinct human Langerhans cell subsets orchestrate reciprocal functions and require different developmental regulation. Immunity. 2021;54:2305‐2320.
Förster R, Davalos‐Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8:362‐371.
Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol. 2014;14:478‐494.
Gaudenzio N, Sibilano R, Marichal T, et al. Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest. 2016;126:3981‐3998.
Galli SJ, Gaudenzio N, Tsai M. Mast cells in inflammation and disease: recent Progress and ongoing concerns. Annu Rev Immunol. 2020;38:49‐77.
Kulka M, Puga NA. Microfluidic generation of lipid nanoparticles to facilitate DNA entry into human mast cells. J Immunol. 2020;204:159.33.
Alam SB, Wang F, Qian H, Kulka M. Apolipoprotein C3 facilitates internalization of cationic lipid nanoparticles into bone marrow‐derived mouse mast cells. Sci Rep. 2023;13:431.
Gaudenzio N, Espagnolle N, Mars LT, Liblau R, Valitutti S, Espinosa E. Cell‐cell cooperation at the T helper cell/mast cell immunological synapse. Blood. 2009;114:4979‐4988.
Gaudenzio N, Laurent C, Valitutti S, Espinosa E. Human mast cells drive memory CD4+ T cells toward an inflammatory IL‐22+ phenotype. J Allergy Clin Immunol. 2013;131:1400‐1407.e11.
Dudeck J, Medyukhina A, Fröbel J, et al. Mast cells acquire MHCII from dendritic cells during skin inflammation. J Exp Med. 2017;214:3791‐3811.
Dudeck A, Köberle M, Goldmann O, et al. Mast cells as protectors of health. J Allergy Clin Immunol. 2019;144:S4‐S18.
McNeil BD, Pundir P, Meeker S, et al. Identification of a mast‐cell‐specific receptor crucial for pseudo‐allergic drug reactions. Nature. 2015;519:237‐241.
Corbière A, Loste A, Gaudenzio N. MRGPRX2 sensing of cationic compounds‐a bridge between nociception and skin diseases? Exp Dermatol. 2021;30:193‐200.
McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID‐19 vaccination: a registry‐based study of 414 cases. J Am Acad Dermatol. 2021;85:46‐55.
Darrigade AS, Théophile H, Sanchez‐Pena P, et al. Sweet syndrome induced by SARS‐CoV‐2 Pfizer‐BioNTech mRNA vaccine. Allergy. 2021;76:3194‐3196.
Zhang HP, Sun YL, Wang YF, et al. Recent developments in the immunopathology of COVID‐19. Allergy. 2023;78:369‐388.
Greenhawt M, Shaker M, Golden DBK, et al. Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID‐19 vaccines: a systematic review and meta‐analysis. Allergy. 2023;78:71‐83.
Soria A, Labella M, Doña I, et al. Risk stratification through extensive allergy work‐up in COVID‐19‐mRNA vaccine allergic reactions. Allergy. 2023;78:2320‐2323.
Gschwandtner M, Mildner M, Mlitz V, et al. Histamine suppresses epidermal keratinocyte differentiation and impairs skin barrier function in a human skin model. Allergy. 2013;68:37‐47.
Kofler L, Forchhammer S. Verzögerte Lokalreaktion mit subkutaner Infiltration nach Impfung mit mRNA‐1273–ein bisher unbeschriebenes Reaktionsmuster eines COVID‐Arms. Hautarzt. 2022;73:488‐490.
Risma KA, Edwards KM, Hummell DS, et al. Potential mechanisms of anaphylaxis to COVID‐19 mRNA vaccines. J Allergy Clin Immunol. 2021;147:2075‐2082.
Kounis NG, Koniari I, de Gregorio C, et al. Allergic reactions to current available COVID‐19 vaccinations: pathophysiology, causality, and therapeutic considerations. Vaccines (Basel). 2021;9:221.
Davids V, Hanekom WA, Mansoor N, et al. The effect of bacille Calmette‐Guérin vaccine strain and route of administration on induced immune responses in vaccinated infants. J Infect Dis. 2006;193:531‐536.
Lesterhuis WJ, de Vries IJM, Schreibelt G, et al. Route of administration modulates the induction of dendritic cell vaccine‐induced antigen‐specific T cells in advanced melanoma patients. Clin Cancer Res. 2011;17:5725‐5735.
Raude E. Développement, validation et caractérisation d'un modèle ex vivo de peau humaine perfusé. FlowSkin. 2020:230‐239. https://theses.hal.science/tel‐03185460
Bastarache JA, Koyama T, Wickersham NE, Ware LB. Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples. J Immunol Methods. 2014;408:13‐23.
Zhang X, Smits AH, van Tilburg GB, Ovaa H, Huber W, Vermeulen M. Proteome‐wide identification of ubiquitin interactions using UbIA‐MS. Nat Protoc. 2018;13:530‐550.
Hubert M, Rousseeuw PJ, Verboven S. A fast method for robust principal components with applications to chemometrics. Chemom Intell Lab Syst. 2002;60:101‐111.
Ritchie ME, Phipson B, Wu D, et al. Limma powers differential expression analyses for RNA‐sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.
Ulgen E, Ozisik O, Sezerman OU. pathfindR: An R package for comprehensive identification of enriched pathways in omics data through active subnetworks. Front Genet. 2019;10:1‐16. https://www.frontiersin.org/articles/10.3389/fgene.2019.00858
Ewels P, Magnusson M, Lundin S, Käller M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics. 2016;32:3047‐3048.
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA‐seq aligner. Bioinformatics. 2013;29:15‐21.
Danecek P, Bonfield JK, Liddle J, et al. Twelve years of SAMtools and BCFtools. GigaScience. 2021;10:giab008.
Putri GH, Anders S, Pyl PT, Pimanda JE, Zanini F. Analysing high‐throughput sequencing data in python with HTSeq 2.0. Bioinformatics. 2022;38:2943‐2945.
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA‐seq data with DESeq2. Genome Biol. 2014;15:550.
Zhang Y, Parmigiani G, Johnson WE. ComBat‐seq: batch effect adjustment for RNA‐seq count data. NAR Genomics and Bioinformatics. 2020;2:lqaa078.
Zheng GXY, Terry JM, Belgrader P, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017;8:14049.
Corbett KS, Edwards DK, Leist SR, et al. SARS‐CoV‐2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020;586:567‐571.
Fleming SJ, Chaffin MD, Arduini A, et al. Unsupervised removal of systematic background noise from droplet‐based single‐cell experiments using CellBender. Nature Methods. 2023;20:1323‐1335. https://www.biorxiv.org/content/10.1101/791699v2.
Hao Y, Hao S, Andersen‐Nissen E, et al. Integrated analysis of multimodal single‐cell data. Cell. 2021;184:3573‐3587.
Choudhary S, Satija R. Comparison and evaluation of statistical error models for scRNA‐seq. Genome Biol. 2022;23:27.
Korsunsky I, Millard N, Fan J, et al. Fast, sensitive and accurate integration of single‐cell data with harmony. Nat Methods. 2019;16:1289‐1296.
Cao J, Spielmann M, Qiu X, et al. The single‐cell transcriptional landscape of mammalian organogenesis. Nature. 2019;566:496‐502.
Wickham H. ggplot2 [Internet]. Cham: Springer International Publishing. 2016. http://link.springer.com/10.1007/978‐3‐319‐24277‐4.
Foroushani A, Agrahari R, Docking R, et al. Large‐scale gene network analysis reveals the significance of extracellular matrix pathway and homeobox genes in acute myeloid leukemia: an introduction to the Pigengene package and its applications. BMC Med Genet. 2017;10:16.
Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847‐2849.
Hunter JD. Matplotlib: a 2D graphics environment. Comput Sci Eng. 2007;9:90‐95.
Waskom ML. seaborn: statistical data visualization. J Open Source Softw. 2021;6:3021.

Auteurs

Manon Scholaert (M)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.
Genoskin SAS, Toulouse, France.

Mathias Peries (M)

Genoskin SAS, Toulouse, France.

Emilie Braun (E)

Genoskin SAS, Toulouse, France.

Jeremy Martin (J)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.

Nadine Serhan (N)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.

Alexia Loste (A)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.

Audrey Bruner (A)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.

Lilian Basso (L)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.

Benoît Chaput (B)

Department of Plastic, Reconstructive and Aesthetic Surgery, Rangueil Hospital, CHU Toulouse, Toulouse, France.

Eric Merle (E)

Genoskin Inc, Salem, Massachusetts, USA.

Pascal Descargues (P)

Genoskin Inc, Salem, Massachusetts, USA.

Emeline Pagès (E)

Genoskin SAS, Toulouse, France.

Nicolas Gaudenzio (N)

Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291-CNRS UMR5051, University Toulouse III, Toulouse, France.
Genoskin SAS, Toulouse, France.

Classifications MeSH