Host transcriptome profiling reveals the IL1RAP as a potential candidate gene for the resistance against Lumpy Skin Disease

Host transcriptome profiling reveals the IL1RAP as a potential candidate gene for the resistance against Lumpy Skin Disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Host transcriptome profiling reveals the IL1RAP as a potential candidate gene for the resistance against Lumpy Skin Disease Mohammad Hossein Banabazi, Steven Van Borm, Tomas Klingström, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3528273/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract To better understand the mechanisms underlying the response diversity to Lumpy Skin Disease Virus (LSDV), we studied differentially expressed genes (DEGs) between two recovered versus three non-recovered Holstein bulls before the infection challenge and three time points after that. The host transcriptome profiling revealed that IL1RAP gene expression could be a potential determinant in distinguishing between resilient and susceptible cattle (p adj < 0.05). It was significantly shifted from up-regulated prior to infection to down-regulated three days post-infection in the LSD-resilient cattle. Its expression remained up-regulated among the susceptible cattle post-infection compared to pre-infection. The results showed that seven days post-infection may be a critical time point for LSD infection. The Gene Ontology (GO) and KEGG pathway enrichment test showed a few enriched GO terms and pathways relevant to the LSD and the involvement of the IL1RAP gene. This pilot study, with limited statistical power, is the first to investigate bovine gene expression profiling in response to LSDV and needs a larger independent trial to confirm the findings. Cattle Lumpy Skin Disease (LSD) IL1RAP gene Transcriptome Profiling Host Determinants Differentially Expressed Genes (DEGs) Introduction Lumpy skin disease (LSD), an acute or subacute systemic viral disease of cattle, is a major global health threat to livestock (Turan et al. 2017 ). LSD was first diagnosed in 1929 in Zambia and spread into the Middle East in 2012 and Europe in 2015 (Anwar et al. 2022 ). Since 2019, LSD recombinant virus strains are spreading in large parts of Asia (Vandenbussche et al. 2022 ). There is host variation in the response of cattle to LSDV infection in field studies (Authority et al. 2020 ). Around 50% of the animals have no clinical signs (asymptomatic) in experimental studies. To better understand the mechanisms underlying the response diversity, we studied the differentially expressed genes (DEGs) between symptomatic and asymptomatic cattle at each time point before and after virus challenge as well as among non-recovered animals over time. Material and Methods Five Holstein bulls were sampled for whole blood using Tempus™ Blood RNA Tubes (ThermoFisher Scientific) and experimentally infected five days later at Sciensano (Belgium) with LSDV via injection in the vena jugularis and the neck with a LSDV strain derived from Israel (Haegeman et al. 2021 ). Three bulls showed LSD symptoms, and two did not. All bulls were also sampled three, seven, and fifteen days post-infection (dpi). Twenty whole RNA samples were isolated using the Tempus™ Spin RNA Isolation Reagent Kit (ThermoFisher Scientific) according to the manufacturer's instructions. All RNA showed RNA Integrity Number equivalent (RINe) scores above 9.0 (High Sensitivity RNA ScreenTape assay, Agilent Technologies). RNA sequencing was performed through a QuantSeq approach (Moll et al. 2014 ) by Illumina NextSeq500 using a 150 HO sequencing kit at the Neuromics Support Facility of VIB University of Antwerp, Center for Molecular Neurology, Belgium. This method results in a single unique fragment per transcript, thus simplifying the quantification of gene expression. After data quality control using FastQC v0.11.8, the 150-bp single reads were trimmed using bbduk.sh script available in BBMAP suite v38.94 (Bushnell 2014 ). The filtered reads were mapped on the Bos taurus reference genome (ARS-UCD1.2, Ensemble release 105) by HISAT2 aligner (Kim et al. 2019 ). The features included in the Bos taurus annotation (the same release) were counted on the individual assembled transcriptomes by featureCounts v2.0.1(Liao et al. 2014 ). Raw read counts were normalized and Differential Gene Expression (DGE) analysis was performed for the asymptomatic versus symptomatic contrasts in each time point as well as for symptomatic animals in each post-infection time point versus pre-infection time using the DESeq2 v1.32.0 package (Love et al. 2014 ) under R v. 4.1.3 (Team 2010 ). The former contrasts reveal the genes involved in the susceptibility to disease, and the last show which genes would be involved when the infection is induced and evolves to symptomatic LSD. After differential expression analysis, the resulting p-values were adjusted for multiple testing using the Benjamini–Hochberg procedure. DEGs with adjusted p-values < 0.05 were considered significant. Gene Set Enrichment Analyses were done for gene ontology terms (GO) and KEGG pathways through R packages: clusterProfiler v4.2.2 (Wu et al. 2021 ) and org.Bt.eg.db V3.14.0 (Carlson 2011 ). Results and discussion On average 25.6 million reads per sample were generated by sequencing. The raw reads were minimally trimmed about 0.7% of total numbers. The filtered reads were aligned on the reference genome in an average rate of 95.4% (Supplementary Table S1). One symptomatic sample on three dpi was recognized as an outlier in Principle Component Analysis (PCA) and removed (Supplementary Figures S1 and S2). This sample had the lowest RNA concentration. The alignment rate for all samples was 95,4% on average. The asymptomatic vs. symptomatic contrasts revealed that 20, 34, 364, and 37 genes were significantly differentially expressed (p adj < 0.05) five days prior to (pre-infection), three, seven, and fifteen days post-infection (dpi), respectively (Supplementary Table S2, and Supplementary Figures S3-A). Differentially expressed genes (DEGs) in the pre-infection time point reveal good candidate determinants for susceptibility to LSD. They are expressed without the infection being present but may be predictors for disease outcome. The experimental infection may influence in the gene expression and activate GO and pathways that do not necessarily result from the induced infection and propose confounding determinants. The symptomatic vs. asymptomatic contrast on pre-infection revealed a few DEGs with an interesting trend. For example, Interleukin 1 Receptor Accessory Protein (IL1RAP) gene was significantly down-regulated five days pre-infection (p adj < 0.05) in cattle that showed the symptoms after challenge (susceptible) but was up-regulated three dpi in the same animals. This gene is located on chromosome one and includes twelve exons ordered as four transcripts. IL1RAP is an essential regulator of redox homeostasis and a cell-surface protein best known as a co-receptor for IL1R signaling (Käll et al. 2007 ). Table 1 also shows that IL1RAP was differentially up-regulated at each time point post-infection versus pre-infection among symptomatic animals (p adj < 0.05). It can be concluded that IL1RAP may have a key role both in LSD susceptibility and the control of the disease. Table 1 Gene expression of IL1RAP gene ( ENSBTAG00000013205 ) in different contrasts (p adj < 0.05) Contrast log 2 FC pvalue padj Symp vs. Asymp (BaseMean = 21.432) pre-infection -20.158 6.55E-11 2.28E-07 3 dpi 19.558 1.28E-08 3.81E-05 7 dpi 0.389 0.89 0.99 15 dpi -0.990 0.73 1 Symptomatic overtime (Post-infection vs. pre-infection) (BaseMean = 21.528) 3dpi vs. pre-infection 14.998 8.25E-07 0.0022 7dpi vs. pre-infection 17.296 1.19E-08 2.08E-05 15dpi vs. pre-infection 15.721 2.27E-07 0.00034 There were the highest number of significant DEGs (p adj < 0.05) and the relatively low number of shared ones with other time points on the seventh day post-infection (Supplementary Tables S2 and S3, Supplementary Figures S3-A, S3-B, S4-A and S4-B). In addition, the enriched GO terms, were only in symptomatic animals vs. pre-infection ones on 7dpi (Supplementary Figure S3-B). They were mostly relevant to immune responses. These results indicate that day 7 is critical in LSD infection. Differential expression of IL1RAP show subsequent enrichment for the cytokine-cytokine receptor interaction pathway with five other DEGs (p adj < 0.05) between symptomatic animals on seven dpi compared to pre-infection time (Supplementary Figure S6-B2, and S7). The therapeutic potential of targeting interleukin-1 family cytokines has been suggested in chronic human inflammatory skin diseases that show similar symptoms to LSD (Calabrese et al. 2022 ). It was suggested as promising target for immunotherapy of metastasis (Zhang et al. 2021 ) using antibodies in humans (Robbrecht et al. 2022 ). Conclusion and Suggestion The expression of IL1RAP prior to any LSD outbreak may promise to distinguish the resilient and susceptible cattle for LSD through a high-resolution and low false discovery rate (FDR) diagnostic Real-time PCR test. Some human studies have already shown its involvement in similar diseases. In ongoing studies, whole transcriptome sequencing for more animals will facilitate analysis of these contrasts with more statistical power and associated variant calling on the transcriptome sequences. Declarations Funding: This project was funded by the European Union's Horizon 2020 research and innovation program under agreement No 773701. Acknowledgments: Special gratitude to the animal caretakers of the Experimental Centre of Sciensano (Belgium) for collecting the data and samples, RNA sequencing was professionally performed at the VIB Neuromics Support Facility (University of Antwerp, Center for Molecular Neurology, Belgium). The authors thank the SLU Bioinformatics Infrastructure, Uppsala, Sweden for the bioinformatics support. We are very grateful to the Kimron Veterinary Institute (Israel) and the Field Israeli Veterinary Services for providing us with the LSDV strain LSD/OA3-Ts. MORAN. M. seed pass.4.155920/2012.20.1.13. Conflict of interest: The authors declare they have no conflict of interest. Data availability statement: Raw RNA-Seq reads are publicly available on the EBI ArrayExpress depository (https://www.ebi.ac.uk/biostudies/arrayexpress/) with accession number E-MTAB-12547. References Anwar A, Na-Lampang K, Preyavichyapugdee N, Punyapornwithaya V (2022) Lumpy Skin Disease Outbreaks in Africa, Europe, and Asia (2005–2022): Multiple Change Point Analysis and Time Series Forecast. Viruses 14:2203 Authority EFS, Calistri P, De Clercq K, et al (2020) Lumpy skin disease epidemiological report IV: Data collection and analysis. Efsa J 18:e06010 Bushnell B (2014) BBMap: a fast, accurate, splice-aware aligner. Lawrence Berkeley National Lab.(LBNL), Berkeley, CA (United States) Calabrese L, Fiocco Z, Satoh TK, et al (2022) Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases. Br J Dermatol 186:925–941 Carlson M (2011) org. Bt. eg. db: Genome wide annotation for Bovine. R Packag. version 3.8. 2 Haegeman A, De Leeuw I, Mostin L, et al (2021) Comparative evaluation of lumpy skin disease virus-based live attenuated vaccines. Vaccines 9:473 Käll L, Canterbury JD, Weston J, et al (2007) Semi-supervised learning for peptide identification from shotgun proteomics datasets. Nat Methods 4:923–925 Kim D, Paggi JM, Park C, et al (2019) Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 37:907–915 Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930 Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:1–21 Moll P, Ante M, Seitz A, Reda T (2014) QuantSeq 3′ mRNA sequencing for RNA quantification Robbrecht D, Jungels C, Sorensen MM, et al (2022) First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer 126:1010–1017 Team RDC (2010) R: A language and environment for statistical computing. Foundation for Statistical Computing, Vienna, Austria. Turan N, Yilmaz A, Tekelioglu BK, Yilmaz H (2017) Lumpy skin disease: global and Turkish perspectives. Approaches Poultry, Dairy Vet Sci 1 Vandenbussche F, Mathijs E, Philips W, et al (2022) Recombinant LSDV strains in Asia: vaccine spillover or natural emergence? Viruses 14:1429 Wu T, Hu E, Xu S, et al (2021) clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov 2 Zhang HF, Hughes CS, Li W, et al (2021) Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. Cancer Discov, 11 (11), 2884-2903 Supplementary Files TableS1statisticsofsequencereads.xlsx Table S1 (Additional Excel File 1). The statistics of the sequence reads per sample. The total number of raw reads, the number of filtered reads, the trimming rate (%), and the overall alignment rate (%). TableS2SDESympvsAsymp.xlsx Table S2 (Additional Excel File 2). The significant Differentially Expressed Genes (SDEGs) between symptomatic and asymptomatic cattle at five days pre-infection, three, seven, and fifteen days post-infection time points (padj < 0.05). TableS3SDEOvertimedpivspre.infected.xlsx Table S3 (Additional Excel File 3). The significant Differentially Expressed Genes (SDEGs) among symptomatic cattle over time post-infection vs. pre-infection (padj < 0.05). SupplementaryFigures.pdf Supplementary Figures: Figure S1. PCA plots of all samples (A) and without the outlier sample (B). Figure S2. Heatmap of the distribution of all samples (A) and without the outlier simple (B). Figure S3. Volcano graphs of the statistically significant Differentially Expressed Genes (SDEGs), indicated by red dots, between symptomatic and asymptomatic animals (padj< 0,05) five days pre-infection, three, seven and fifteen days post-infection (A), and among symptomatic cattle (padj < 0.05) over time (B). Figure S4. Venn diagram of the shared numbers of the Significant Differentially Expressed Genes (SDEGs) between symptomatic vs. asymptomatic animals five days pre-infection, three, seven, and fifteen days post-infection (A), and among symptomatic cattle over time (B). Figure S5. Gene Ontology (GO) enrichment test (padj < 0,05) for the symptomatic vs. asymptomatic contrasts (A) and symptomatic cattle over time (B). Figure S6. KEGG pathway enrichment test (padj< 0.05) for the symptomatic vs. asymptomatic contrasts (A) and symptomatic cattle over time (B). Figure S7. The KEGG view on the cytokine-cytokine receptor interaction pathway (bta04060) enriched seven days post-infection among symptomatic cattle (padj< 0.05). Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3528273","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":244583724,"identity":"233ff232-e791-47a4-abf8-09d2f34b60f9","order_by":0,"name":"Mohammad Hossein Banabazi","email":"","orcid":"https://orcid.org/0000-0002-7873-8123","institution":"Sveriges lantbruksuniversitet (SLU)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Hossein","lastName":"Banabazi","suffix":""},{"id":244585039,"identity":"df32b04a-254d-48b2-9f50-e00735211eed","order_by":1,"name":"Steven Van Borm","email":"","orcid":"https://orcid.org/0000-0002-3464-2306","institution":"Sciensano","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Steven","middleName":"Van","lastName":"Borm","suffix":""},{"id":244587433,"identity":"490d8ed3-5fd9-42af-ac91-d78970ddc97d","order_by":2,"name":"Tomas Klingström","email":"","orcid":"https://orcid.org/0000-0002-9504-1352","institution":"Sveriges lantbruksuniversitet (SLU)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomas","middleName":"","lastName":"Klingström","suffix":""},{"id":244591130,"identity":"b95b15e3-bfbf-4492-9e96-b8a98bace42c","order_by":3,"name":"Adnan Niazi","email":"","orcid":"https://orcid.org/0000-0003-0311-5279","institution":"Sveriges lantbruksuniversitet (SLU)","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Adnan","middleName":"","lastName":"Niazi","suffix":""},{"id":244591131,"identity":"2e0243e3-2b58-434f-8803-910c97eaeefd","order_by":4,"name":"Kris De Clercq","email":"","orcid":"https://orcid.org/0000-0002-2928-3521","institution":"Sciensano","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kris","middleName":"","lastName":"De Clercq","suffix":""},{"id":244591132,"identity":"86e63865-e676-40bc-a27d-c6392c9b6f49","order_by":5,"name":"Laurent Mostin","email":"","orcid":"https://orcid.org/0009-0006-0789-2656","institution":"Sciensano","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Laurent","middleName":"","lastName":"Mostin","suffix":""},{"id":244591133,"identity":"2e1895e5-af18-430a-9b82-38b63a8e5dd2","order_by":6,"name":"Andy Haegeman","email":"","orcid":"https://orcid.org/0000-0003-4056-214X","institution":"Sciensano","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Andy","middleName":"","lastName":"Haegeman","suffix":""},{"id":244591134,"identity":"1de1490c-be67-403c-9699-0fb50ae0db68","order_by":7,"name":"Dirk-Jan De Koning","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIie3RMQrCMBiG4a8E6lJ1DYg9QySgFgWvoksne4eK0Elx9RgeoRIoDgXXjoKjS0aHIqYRB5fEUTDvlEAekp8ALtcPNiM5KCAAonYSYzsZpJoUmnj7Zm2L5ZqUekOCL4lXSVThqNUWt2lNF2lX5DZCoj0kj9adeJJkitB4biN+r/2Qi4MIhjxJGxIwO6lRvchYP+wszeSkiBq/IfwKXxEsjQKD7WodbVBwpm7xthnlGY3ND5u1yLG6Q4TsXHJ5r6f9XVdczNfAS98rX3+Kbzn/ETGP7XK5XH/bE4SDSCOasUrtAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6343-8155","institution":"Sveriges lantbruksuniversitet (SLU)","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Dirk-Jan","middleName":"","lastName":"De Koning","suffix":""}],"badges":[],"createdAt":"2023-10-31 19:45:46","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-3528273/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3528273/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":45642912,"identity":"1aac2ed2-060c-418a-91d2-4f950828486d","added_by":"auto","created_at":"2023-11-01 11:02:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":232287,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3528273/v1/41c1fc9f-20ac-4725-a149-6216cb11e97c.pdf"},{"id":45642693,"identity":"6e3fd1c5-d24d-4827-8061-359ae604382a","added_by":"auto","created_at":"2023-11-01 10:54:30","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21265,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1 (Additional Excel File 1). \u003c/strong\u003eThe statistics of the sequence reads per sample. The total number of raw reads, the number of filtered reads, the trimming rate (%), and the overall alignment rate (%).\u003c/p\u003e","description":"","filename":"TableS1statisticsofsequencereads.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3528273/v1/41c6025173b2ba5c0af1bed8.xlsx"},{"id":45642694,"identity":"6ec021a0-ac5d-4bd1-ab39-54f789b766ea","added_by":"auto","created_at":"2023-11-01 10:54:30","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":65976,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S2 (Additional Excel File 2). \u003c/strong\u003eThe significant Differentially Expressed Genes (SDEGs) between symptomatic and asymptomatic cattle at five days pre-infection, three, seven, and fifteen days post-infection time points (padj \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"TableS2SDESympvsAsymp.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3528273/v1/92fcde97de070987f0dc7540.xlsx"},{"id":45642692,"identity":"7f135fb1-7f63-4f89-8025-366dab2a1388","added_by":"auto","created_at":"2023-11-01 10:54:30","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":25346,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S3 (Additional Excel File 3). \u003c/strong\u003eThe significant Differentially Expressed Genes (SDEGs) among symptomatic cattle over time post-infection vs. pre-infection (padj \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"TableS3SDEOvertimedpivspre.infected.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3528273/v1/34f33667acbe27275c68714c.xlsx"},{"id":45642695,"identity":"38a58d33-d82f-4516-85d9-5f8595f9048d","added_by":"auto","created_at":"2023-11-01 10:54:30","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1487645,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S1.\u003c/strong\u003e PCA plots of all samples (A) and without the outlier sample (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S2.\u003c/strong\u003e Heatmap of the distribution of all samples (A) and without the outlier simple (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S3.\u003c/strong\u003e Volcano graphs of the statistically significant Differentially Expressed Genes (SDEGs), indicated by red dots, between symptomatic and asymptomatic animals (padj\u0026lt; 0,05) five days pre-infection, three, seven and fifteen days post-infection (A), and among symptomatic cattle (padj \u0026lt; 0.05) over time (B).\u003c/p\u003e\n\u003cp\u003eFigure S4. Venn diagram of the shared numbers of the Significant Differentially Expressed Genes (SDEGs) between symptomatic vs. asymptomatic animals five days pre-infection, three, seven, and fifteen days post-infection (A), and among symptomatic cattle over time (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S5. \u003c/strong\u003eGene Ontology (GO) enrichment test (padj \u0026lt; 0,05) for the symptomatic vs. asymptomatic contrasts (A) and symptomatic cattle over time (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S6. \u003c/strong\u003eKEGG pathway enrichment test (padj\u0026lt; 0.05) for the symptomatic vs. asymptomatic contrasts (A) and symptomatic cattle over time (B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure S7.\u003c/strong\u003e The KEGG view on the cytokine-cytokine receptor interaction pathway (bta04060) enriched seven days post-infection among symptomatic cattle (padj\u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"SupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3528273/v1/6349d80fcababb901af553e2.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003e\u003cstrong\u003eHost transcriptome profiling reveals the IL1RAP as a potential candidate gene for the resistance against Lumpy Skin Disease\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLumpy skin disease (LSD), an acute or subacute systemic viral disease of cattle, is a major global health threat to livestock (Turan et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). LSD was first diagnosed in 1929 in Zambia and spread into the Middle East in 2012 and Europe in 2015 (Anwar et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Since 2019, LSD recombinant virus strains are spreading in large parts of Asia (Vandenbussche et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). There is host variation in the response of cattle to LSDV infection in field studies (Authority et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Around 50% of the animals have no clinical signs (asymptomatic) in experimental studies. To better understand the mechanisms underlying the response diversity, we studied the differentially expressed genes (DEGs) between symptomatic and asymptomatic cattle at each time point before and after virus challenge as well as among non-recovered animals over time.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003eFive Holstein bulls were sampled for whole blood using Tempus\u0026trade; Blood RNA Tubes (ThermoFisher Scientific) and experimentally infected five days later at Sciensano (Belgium) with LSDV via injection in the vena jugularis and the neck with a LSDV strain derived from Israel (Haegeman et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Three bulls showed LSD symptoms, and two did not. All bulls were also sampled three, seven, and fifteen days post-infection (dpi). Twenty whole RNA samples were isolated using the Tempus\u0026trade; Spin RNA Isolation Reagent Kit (ThermoFisher Scientific) according to the manufacturer's instructions. All RNA showed RNA Integrity Number equivalent (RINe) scores above 9.0 (High Sensitivity RNA ScreenTape assay, Agilent Technologies). RNA sequencing was performed through a QuantSeq approach (Moll et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) by Illumina NextSeq500 using a 150 HO sequencing kit at the Neuromics Support Facility of VIB University of Antwerp, Center for Molecular Neurology, Belgium. This method results in a single unique fragment per transcript, thus simplifying the quantification of gene expression. After data quality control using FastQC v0.11.8, the 150-bp single reads were trimmed using bbduk.sh script available in BBMAP suite v38.94 (Bushnell \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The filtered reads were mapped on the \u003cem\u003eBos taurus\u003c/em\u003e reference genome (ARS-UCD1.2, Ensemble release 105) by HISAT2 aligner (Kim et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The features included in the \u003cem\u003eBos taurus\u003c/em\u003e annotation (the same release) were counted on the individual assembled transcriptomes by featureCounts v2.0.1(Liao et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Raw read counts were normalized and Differential Gene Expression (DGE) analysis was performed for the asymptomatic versus symptomatic contrasts in each time point as well as for symptomatic animals in each post-infection time point versus pre-infection time using the DESeq2 v1.32.0 package (Love et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) under R v. 4.1.3 (Team \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). The former contrasts reveal the genes involved in the susceptibility to disease, and the last show which genes would be involved when the infection is induced and evolves to symptomatic LSD. After differential expression analysis, the resulting p-values were adjusted for multiple testing using the Benjamini\u0026ndash;Hochberg procedure. DEGs with adjusted p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant. Gene Set Enrichment Analyses were done for gene ontology terms (GO) and KEGG pathways through R packages: clusterProfiler v4.2.2 (Wu et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) and org.Bt.eg.db V3.14.0 (Carlson \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eOn average 25.6\u0026nbsp;million reads per sample were generated by sequencing. The raw reads were minimally trimmed about 0.7% of total numbers. The filtered reads were aligned on the reference genome in an average rate of 95.4% (Supplementary Table S1). One symptomatic sample on three dpi was recognized as an outlier in Principle Component Analysis (PCA) and removed (Supplementary Figures S1 and S2). This sample had the lowest RNA concentration. The alignment rate for all samples was 95,4% on average. The asymptomatic vs. symptomatic contrasts revealed that 20, 34, 364, and 37 genes were significantly differentially expressed (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05) five days prior to (pre-infection), three, seven, and fifteen days post-infection (dpi), respectively (Supplementary Table S2, and Supplementary Figures S3-A).\u003c/p\u003e \u003cp\u003eDifferentially expressed genes (DEGs) in the pre-infection time point reveal good candidate determinants for susceptibility to LSD. They are expressed without the infection being present but may be predictors for disease outcome. The experimental infection may influence in the gene expression and activate GO and pathways that do not necessarily result from the induced infection and propose confounding determinants. The symptomatic vs. asymptomatic contrast on pre-infection revealed a few DEGs with an interesting trend. For example, Interleukin 1 Receptor Accessory Protein (IL1RAP) gene was significantly down-regulated five days pre-infection (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05) in cattle that showed the symptoms after challenge (susceptible) but was up-regulated three dpi in the same animals. This gene is located on chromosome one and includes twelve exons ordered as four transcripts. IL1RAP is an essential regulator of redox homeostasis and a cell-surface protein best known as a co-receptor for IL1R signaling (K\u0026auml;ll et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2007\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e also shows that IL1RAP was differentially up-regulated at each time point post-infection versus pre-infection among symptomatic animals (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05). It can be concluded that IL1RAP may have a key role both in LSD susceptibility and the control of the disease.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGene expression of \u003cem\u003eIL1RAP\u003c/em\u003e gene (\u003cem\u003eENSBTAG00000013205\u003c/em\u003e) in different contrasts (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eContrast\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003elog\u003csub\u003e2\u003c/sub\u003eFC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003epvalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003epadj\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cb\u003eSymp vs. Asymp\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(BaseMean\u0026thinsp;=\u0026thinsp;21.432)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003epre-infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-20.158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.55E-11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.28E-07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3 dpi\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.558\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.28E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.81E-05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e7 dpi\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e15 dpi\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eSymptomatic overtime\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(Post-infection vs. pre-infection)\u003c/p\u003e \u003cp\u003e(BaseMean\u0026thinsp;=\u0026thinsp;21.528)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3dpi vs. pre-infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.25E-07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e7dpi vs. pre-infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19E-08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.08E-05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e15dpi vs. pre-infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.27E-07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.00034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere were the highest number of significant DEGs (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05) and the relatively low number of shared ones with other time points on the seventh day post-infection (Supplementary Tables S2 and S3, Supplementary Figures S3-A, S3-B, S4-A and S4-B). In addition, the enriched GO terms, were only in symptomatic animals vs. pre-infection ones on 7dpi (Supplementary Figure S3-B). They were mostly relevant to immune responses. These results indicate that day 7 is critical in LSD infection.\u003c/p\u003e \u003cp\u003eDifferential expression of \u003cem\u003eIL1RAP\u003c/em\u003e show subsequent enrichment for the cytokine-cytokine receptor interaction pathway with five other DEGs (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05) between symptomatic animals on seven dpi compared to pre-infection time (Supplementary Figure S6-B2, and S7). The therapeutic potential of targeting interleukin-1 family cytokines has been suggested in chronic human inflammatory skin diseases that show similar symptoms to LSD (Calabrese et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). It was suggested as promising target for immunotherapy of metastasis (Zhang et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) using antibodies in humans (Robbrecht et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion and Suggestion","content":"\u003cp\u003eThe expression of \u003cem\u003eIL1RAP\u003c/em\u003e prior to any LSD outbreak may promise to distinguish the resilient and susceptible cattle for LSD through a high-resolution and low false discovery rate (FDR) diagnostic Real-time PCR test. Some human studies have already shown its involvement in similar diseases. In ongoing studies, whole transcriptome sequencing for more animals will facilitate analysis of these contrasts with more statistical power and associated variant calling on the transcriptome sequences.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This project was funded by the European Union\u0026apos;s Horizon 2020 research and innovation program under agreement No 773701.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eSpecial gratitude to the animal caretakers of the Experimental Centre of Sciensano (Belgium) for collecting the data and samples, RNA sequencing was professionally performed at the VIB Neuromics Support Facility (University of Antwerp, Center for Molecular Neurology, Belgium).\u0026nbsp;The authors thank the SLU Bioinformatics Infrastructure, Uppsala, Sweden for the bioinformatics support. We are very grateful to the Kimron Veterinary Institute (Israel) and the Field Israeli Veterinary Services for providing us with the LSDV strain LSD/OA3-Ts. MORAN. M. seed pass.4.155920/2012.20.1.13.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e The authors declare they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e Raw RNA-Seq reads are publicly available on the EBI ArrayExpress depository (https://www.ebi.ac.uk/biostudies/arrayexpress/) with accession number E-MTAB-12547. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAnwar A, Na-Lampang K, Preyavichyapugdee N, Punyapornwithaya V (2022) Lumpy Skin Disease Outbreaks in Africa, Europe, and Asia (2005\u0026ndash;2022): Multiple Change Point Analysis and Time Series Forecast. Viruses 14:2203\u003c/li\u003e\n\u003cli\u003eAuthority EFS, Calistri P, De Clercq K, et al (2020) Lumpy skin disease epidemiological report IV: Data collection and analysis. Efsa J 18:e06010\u003c/li\u003e\n\u003cli\u003eBushnell B (2014) BBMap: a fast, accurate, splice-aware aligner. Lawrence Berkeley National Lab.(LBNL), Berkeley, CA (United States)\u003c/li\u003e\n\u003cli\u003eCalabrese L, Fiocco Z, Satoh TK, et al (2022) Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases. Br J Dermatol 186:925\u0026ndash;941\u003c/li\u003e\n\u003cli\u003eCarlson M (2011) org. Bt. eg. db: Genome wide annotation for Bovine. R Packag. version 3.8. 2\u003c/li\u003e\n\u003cli\u003eHaegeman A, De Leeuw I, Mostin L, et al (2021) Comparative evaluation of lumpy skin disease virus-based live attenuated vaccines. Vaccines 9:473\u003c/li\u003e\n\u003cli\u003eK\u0026auml;ll L, Canterbury JD, Weston J, et al (2007) Semi-supervised learning for peptide identification from shotgun proteomics datasets. Nat Methods 4:923\u0026ndash;925\u003c/li\u003e\n\u003cli\u003eKim D, Paggi JM, Park C, et al (2019) Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol 37:907\u0026ndash;915\u003c/li\u003e\n\u003cli\u003eLiao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923\u0026ndash;930\u003c/li\u003e\n\u003cli\u003eLove MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:1\u0026ndash;21\u003c/li\u003e\n\u003cli\u003eMoll P, Ante M, Seitz A, Reda T (2014) QuantSeq 3\u0026prime; mRNA sequencing for RNA quantification\u003c/li\u003e\n\u003cli\u003eRobbrecht D, Jungels C, Sorensen MM, et al (2022) First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. Br J Cancer 126:1010\u0026ndash;1017\u003c/li\u003e\n\u003cli\u003eTeam RDC (2010) R: A language and environment for statistical computing. Foundation for Statistical Computing, Vienna, Austria.\u003c/li\u003e\n\u003cli\u003eTuran N, Yilmaz A, Tekelioglu BK, Yilmaz H (2017) Lumpy skin disease: global and Turkish perspectives. Approaches Poultry, Dairy Vet Sci 1\u003c/li\u003e\n\u003cli\u003eVandenbussche F, Mathijs E, Philips W, et al (2022) Recombinant LSDV strains in Asia: vaccine spillover or natural emergence? Viruses 14:1429\u003c/li\u003e\n\u003cli\u003eWu T, Hu E, Xu S, et al (2021) clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov 2\u003c/li\u003e\n\u003cli\u003eZhang HF, Hughes CS, Li W, et al (2021) Proteomic Screens for Suppressors of Anoikis Identify IL1RAP as a Promising Surface Target in Ewing Sarcoma. Cancer Discov, 11 (11), 2884-2903\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"The European Union's Horizon 2020 research and innovation program under agreement No 773701","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cattle, Lumpy Skin Disease (LSD), IL1RAP gene, Transcriptome Profiling, Host Determinants, Differentially Expressed Genes (DEGs)","lastPublishedDoi":"10.21203/rs.3.rs-3528273/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3528273/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTo better understand the mechanisms underlying the response diversity to Lumpy Skin Disease Virus (LSDV), we studied differentially expressed genes (DEGs) between two recovered versus three non-recovered Holstein bulls before the infection challenge and three time points after that. The host transcriptome profiling revealed that IL1RAP gene expression could be a potential determinant in distinguishing between resilient and susceptible cattle (p\u003csub\u003eadj\u003c/sub\u003e \u0026lt; 0.05). It was significantly shifted from up-regulated prior to infection to down-regulated three days post-infection in the LSD-resilient cattle. Its expression remained up-regulated among the susceptible cattle post-infection compared to pre-infection. The results showed that seven days post-infection may be a critical time point for LSD infection. The Gene Ontology (GO) and KEGG pathway enrichment test showed a few enriched GO terms and pathways relevant to the LSD and the involvement of the \u003cem\u003eIL1RAP\u003c/em\u003e gene. This pilot study, with limited statistical power, is the first to investigate bovine gene expression profiling in response to LSDV and needs a larger independent trial to confirm the findings.\u003c/p\u003e","manuscriptTitle":"Host transcriptome profiling reveals the IL1RAP as a potential candidate gene for the resistance against Lumpy Skin Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-01 10:54:25","doi":"10.21203/rs.3.rs-3528273/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"92c6e570-b2db-4f93-b1ca-8cf80faf04a6","owner":[],"postedDate":"November 1st, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-11-01T10:54:25+00:00","versionOfRecord":[],"versionCreatedAt":"2023-11-01 10:54:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3528273","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3528273","identity":"rs-3528273","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}