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Exploring Ribosomal Genes as Potential Biomarkers of the Immune Microenvironment in Respiratory Syncytial Virus Infection

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Abstract

Respiratory syncytial virus (RSV) is the most common pathogen causing acute lower respiratory tract infection in infants and children. Due to limited knowledge of the pathological and molecular mechanisms of immunodeficiency underlying RSV disease, there is currently a lack of an approved and effective RSV vaccine to combat RSV infections. This study aimed to identify genes associated with immune dysfunction using bioinformatics methods to gain insights into the role of dysregulated immune genes in RSV disease progression, and to predict potential therapeutic drugs by targeting dysregulated immune-related genes. 423 immune-related differential genes (DEIRGs) were filtered from the blood samples of 87 healthy individuals and 170 RSV patients. According to CIBERSORT analysis, the blood of RSV patients showed increased infiltration of various immune cells. Subsequently, ten immune-related hub genes were screened via Protein–Protein Interaction Networks. Six signature immune-related genes (RPS2, RPS5, RPS13, RPS14, RPS18, and RPS4X) as candidate characteristic genes for the diagnostic model were identified by Lasso regression. The AUC value of the ROC curve of the six signature genes was 0.884. This result, intriguingly, suggested that all six immune-related genes with a good internal validation effect were ribosome family genes. Finally, through molecular docking analyses targeting these differential immune genes, ADO and fluperlapine were found to have high stable binding to major proteins of important immune-related genes in nine drug-protein interactions. Overall, the present study screened immune-related genes that are dysregulated in the development of RSV disease to investigate the pathogenesis of RSV infection from the standpoint of immune disorders. Unexpectedly, bioinformatics analysis revealed that ribosome family genes may be involved in the immune dysregulation of RSV disease, and these genes as targets formed the basis for potential drug modification candidates in RSV disease.

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Data Availability

All datasets provided in this study can be found in the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/).

References

  • Al-Afif A, Alyazidi R, Oldford SA, Huang YY, King CA, Marr N, Haidl ID, Anderson R, Marshall JS (2015) Respiratory syncytial virus infection of primary human mast cells induces the selective production of type I interferons, CXCL10, and CCL4. J Allergy Clin Immun 136(5):1346–1353

    Article  CAS  PubMed  Google Scholar 

  • Alizadehmohajer N, Zahedifar S, Sohrabi E, Shaddel Basir S, Nourigheimasi S, Falak R, Nedaeinia R, Ferns A, G., Emami Nejad, A. and Manian, M. (2023) Using in silico bioinformatics algorithms for the accurate prediction of the impact of spike protein mutations on the pathogenicity, stability, and functionality of the SARS-CoV-2 virus and analysis of potential therapeutic targets. Biochem Genet 61(2):778–808

    Article  CAS  PubMed  Google Scholar 

  • Araki K, Morita M, Bederman AG, Konieczny BT, Kissick HT, Sonenberg N, Ahmed R (2017) Translation is actively regulated during the differentiation of CD8(+) effector T cells. Nature Immun 18(9):1046–1057

    Article  CAS  PubMed  Google Scholar 

  • Aurore CAG, Martin B, Orestes C, Tessa MK, Leonie A, van Djoke G, Putri Ayu F, Gerard HK, Louis B, Rudi WH, van den Maarten B, Martijn CN (2024) Airway epithelial cell response to RSV is mostly impaired in goblet and multiciliated cells in asthma. Thorax 2023:220230

    Google Scholar 

  • Benet T, Picot VS, Messaoudi M, Chou M, Eap T, Wang JW, Shen KL, Pape JW, Rouzier V, Awasthi S, Pandey N, Global Approach Biological R (2017) Microorganisms associated with pneumonia in children < 5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective. Case-Control Study Clin Infect Dis 65(4):604–612

    PubMed  Google Scholar 

  • Brenes-Chacon H, Garcia-Maurino C, Moore-Clingenpeel M, Mertz S, Ye F, Cohen DM, Ramilo O, Mejias A (2021) Age-dependent interactions among clinical characteristics, viral loads and disease severity in young children with respiratory syncytial virus infection. Pediatr Infect Dis J 40(2):116–122

    Article  PubMed  PubMed Central  Google Scholar 

  • Bylsma LC, Suh M, Movva N, Fryzek JP, Nelson CB (2022) Mortality among US infants and children under 5 years of age with respiratory syncytial virus and bronchiolitis: a systematic literature review. J Infect Dis 226(SUPPL 2):S267–S281

    Article  PubMed  PubMed Central  Google Scholar 

  • Chang JJY, Gleeson J, Rawlinson D, De Paoli-Iseppi R, Zhou CX, Mordant FL, Londrigan SL, Clark MB, Subbarao K, Stinear TP, Coin LJM, Pitt ME (2022) Long-read RNA sequencing identifies polyadenylation elongation and differential transcript usage of host transcripts during SARS-CoV-2 in vitro infection. Front Immun 13:832223

    Article  CAS  Google Scholar 

  • Chen H, Boutros PC (2011) VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R. BMC Bioinformat 12:35

    Article  Google Scholar 

  • Chen SS, Tang W, Yu GY, Tang ZZ, Liu EM (2023) CXCL12/CXCR4 axis is involved in the recruitment of NK cells by HMGB1 contributing to persistent airway inflammation and AHR during the late stage of RSV infection. J Micro 61(4):461–469

    Article  CAS  Google Scholar 

  • Churiso G, Husen G, Bulbula D, Abebe L (2022) Immunity cell responses to RSV and the role of antiviral inhibitors: a systematic review. Infect Drug Res 15:7413–7430

    Article  Google Scholar 

  • Deng B, Liao F, Liu Y, He P, Wei S, Liu C, Dong W (2023) Comprehensive analysis of endoplasmic reticulum stress-associated genes signature of ulcerative colitis. Front Immun 14:1158648

    Article  CAS  Google Scholar 

  • Elhamamsy AR, Metge BJ, Alsheikh HA, Shevde LA, Samant RS (2022) Ribosome biogenesis: a central player in cancer metastasis and therapeutic resistance. Cancer Res 82(13):2344–2353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guan JY, Han SC, Wu JE, Zhang Y, Bai MY, Abdullah SW, Sun SQ, Guo HC (2021) Ribosomal protein L13 participates in innate immune response induced by foot-and-mouth disease virus. Front Immun 12:616402

    Article  CAS  Google Scholar 

  • Gupta MR, Kolli D, Garofalo RP (2013) Differential response of BDCA-1(+) and BDCA-3(+) myeloid dendritic cells to respiratory syncytial virus infection. Respiat Res 14(1):71

    Article  CAS  Google Scholar 

  • Hamarsha A, Balachandran K, Sailan AT, Nasruddin NS (2023) Predicting key genes and therapeutic molecular modelling to explain the association between Porphyromonas gingivalis (P. gingivalis) and Alzheimer&rsquo;s Disease (AD). Inter J Mol Sci 24:543

    Article  Google Scholar 

  • Hanzelmann S, Castelo R, Guinney J (2013) GSVA: gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformt 14:7

    Article  Google Scholar 

  • Heinonen S, Rodriguez-Fernandez R, Diaz A, Oliva Rodriguez-Pastor S, Ramilo O, Mejias A (2019) Infant immune response to respiratory viral infections. Immun Aller Clin N Am 39(3):361–376

    Article  Google Scholar 

  • Hermawan A, Putri H (2019) Targets and molecular mechanisms of a citrus flavonoid, hesperidin, against luminal breast cancer cells: an integrative bioinformatics analysis. Asian Pac J Trop Bio 9(12):531–538

    Article  CAS  Google Scholar 

  • Jiao LJ, Liu YZ, Yu XY, Pan XB, Zhang Y, Tu JC, Song YH, Li YX (2023) Ribosome biogenesis in disease: new players and therapeutic targets. S Singal Transduction Tar 8(1):15

    Article  CAS  Google Scholar 

  • Kang J, Brajanovski N, Chan KT, Xuan JC, Pearson RB, Sanij E (2021) Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduct Tar 6(1):323

    Article  CAS  Google Scholar 

  • Kiratzis M, Lai G, Calamita P, Mancino M, Iriti M, Manfrini N, Gallo S (2023) RACK1 release from the ribosome couples translational regulation with starving signaling and possibly depends on phosphorylation of key serine and threonine residues: extra ribosomal RACK1 regulates starving signaling. Cell Mol Biol 69(1):7–12

    Article  PubMed  Google Scholar 

  • Li L, Zhou Y, Huang C, Jian L, Lin Z, Lin L, Li C, Ye Y (2023) Insight into the influence of plant oils on the composition of diacylglycerol fabricated by glycerolysis and esterification. Indus Crop Prod 204:117324

    Article  CAS  Google Scholar 

  • Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database hallmark gene set collection. Cell Syst 1(6):417–425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manti S, Leonardi S, Rezaee F, Harford TJ, Perez MK, Piedimonte G (2022) Effects of vertical transmission of respiratory viruses to the offspring. Front Immunol 13:853009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonald JU, Kaforou M, Clare S, Hale C, Ivanova M, Huntley D, Dorner M, Wright VJ, Levin M, Martinon-Torres F, Herberg JA, Tregoning JS (2016) A simple screening approach to prioritize genes for functional analysis identifies a role for interferon regulatory factor 7 in the control of respiratory syncytial virus disease. Msystems 1(3):e00051-e116

    Article  PubMed  PubMed Central  Google Scholar 

  • Murphy-Schafer AR, Paust S (2021) Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection. Front Cell Inflect Micro 11:580679

    Article  CAS  Google Scholar 

  • Newman AM, Liu CL, Green MR, Gentles AJ, Feng WG, Xu Y, Hoang CD, Diehn M, Alizadeh AA (2015) Robust enumeration of cell subsets from tissue expression profiles. Nature Method 12(5):453–457

    Article  CAS  Google Scholar 

  • O’Brien KL, Levine OS, Knoll MD, Feikin DR, DeLuca AN, Driscoll AJ, Fancourt N, Fu W, Haddix M, Hammitt LL, Higdon MM, Mitchell JL, Grp PS (2019) Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study. Lancet 394(10200):757–779

    Article  Google Scholar 

  • Pan R, Yu C, Shao Y, Hong H, Sun J, Zhang Z, Li P, Zheng M (2022) Identification of key genes and pathways involved in circulating tumor cells in colorectal cancer. Anal Cell Pathol (Amst) 2022:9943571

    PubMed  Google Scholar 

  • Park Y, Kim KH, Lee Y, Lee YT, Kang SM, Ko EJ (2021) Natural killer cells contribute to enhanced respiratory disease after oil-in-water emulsion adjuvanted vaccination against respiratory syncytial virus and infection. Heuman Vac Immun 17(10):3806–3817

    CAS  Google Scholar 

  • Piters W, Heinonen S, Hasrat R, Bunsow E, Smith B, Suarez-Arrabal MC, Chaussabel D, Cohen DM, Sanderl EAM, Ramilo O, Bogaert D, Mejias A (2016) Nasopharyngeal microbiota, host transcriptome, and disease severity in children with respiratory syncytial virus infection. Am J Resp Crit Care 194(9):1104–1115

    Article  CAS  Google Scholar 

  • Ribezzo F, Snoeren IAM, Ziegler S, Stoelben J, Olofsen PA, Henic A, Ferreira MV, Chen S, Stalmann USA, Buesche G, Hoogenboezem RM, Kramann R, Platzbecker U, Raaijmakers M, Ebert BL, Schneider RK (2019) Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q-syndrome. Leukemia 33(7):1759–1772

    Article  CAS  PubMed  Google Scholar 

  • Ritchie ME, Phipson B, Wu D, Hu YF, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):e47

    Article  PubMed  PubMed Central  Google Scholar 

  • Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Muller M (2011) pROC: an open-source package for R and S plus to analyze and compare ROC curves. BMC Bioinform 12:3229

    Article  Google Scholar 

  • Rodriguez-Fernandez R, Tapia LI, Yang CF, Torres JP, Chavez-Bueno S, Garcia C, Jaramillo LM, Moore-Clingenpeel M, Jafri HS, Peeples ME, Piedra PA, Ramilo O, Mejias A (2018) Respiratory syncytial virus genotypes, host immune profiles, and disease severity in young children hospitalized with bronchiolitis. J Infect Dis 217(1):24–34

    Article  CAS  Google Scholar 

  • Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata T, Makino A, Ogata R, Nakamura S, Ito T, Nagata K, Terauchi Y, Oishi T, Fujieda M, Takahashi Y, Ato M (2020) Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization. J Clin Invest 130(6):3021–3037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shiroshita A, Gebretsadik T, Wu P, Kubilay NZ, Hartert TV (2024) Association between age of respiratory syncytial virus infection hospitalization and childhood asthma: A systematic review. PLoS One 19(2):e0296685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. P Natl Acad Sci USA 102(43):15545–15550

    Article  CAS  Google Scholar 

  • Surie D, Yuengling KA, DeCuir J, Zhu YW, Gaglani M, Ginde AA, Talbot HK, Casey JD, Mohr NM, Ghamande S, Gibbs KW, Files C, Hager DN, Ali H, Prekker ME, McMorrow ML, Martin ET, Self WH, Network IVY (2023) Disease severity of respiratory syncytial virus compared with COVID-19 and influenza among hospitalized adults aged ≥60 years—IVY Network, 20 US States, February 2022–May 2023. MMWR-Morbid Mor W 72(40):1083–1088

    Article  Google Scholar 

  • Trott O, Olson AJ (2010) Software news and update AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vyleta ML, Wong J, Magun BE (2012) Suppression of ribosomal function triggers innate immune signaling through activation of the NLRP3 inflammasome. PLoS One 7(5):e36044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Uddin MN, Wang R, Gong YH, Wu Y (2022) Comprehensive analysis and validation of novel immune and vascular remodeling related genes signature associated with drug interactions in pulmonary arterial hypertension. Front Genet 13:922213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu JQ, Xu L, Han X, Hu HY, Qi FF, Bai S, Chai RN, Teng YE, Liu BX (2017) Role of gamma delta T cells in exacerbated airway inflammation during reinfection of neonatally primed mice in adulthood. J Med Virol 89(12):2108–2115

    Article  CAS  PubMed  Google Scholar 

  • Wu Y, Dong X, Hu J, Wang L, Xu R, Wang Y, Zeng Y (2023) Transcriptomics based network analyses and molecular docking highlighted potentially therapeutic biomarkers for colon cancer. Biochem Genet 61(4):1509–1527

    Article  CAS  PubMed  Google Scholar 

  • Yan Y, Jin M, Li S, Wu Y, Wang Q, Hu F, Shen C, Yin W (2023) Hub genes, diagnostic model, and predicted drugs in systemic sclerosis by integrated bioinformatics analysis. Front Genet 14:1202561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang B, Fan J, Huang J, Guo E, Fu Y, Liu S, Xiao RR, Liu C, Lu F, Qin TY, He C, Wang Z, Sun C (2021) Clinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection. Nat Commun 12(1):3501

    Article  CAS  Google Scholar 

  • Yin X, Jiang K, Zhou Z, Yu H, Yan D, He X, Yan S (2023) Prognostic and immunological potential of ribonucleotide reductase subunits in liver cancer. Oxid Med Cell Longev 2023:3878796

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu G, Wang L, Han Y, He Q (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16(5):284–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zanin M, Baviskar P, Webster R, Webby R (2016) The interaction between respiratory pathogens and mucus. Cell Host Microbe 19(2):159–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng D, Ye Z, Shen R, Yu G, Wu J, Xiong Y, Zhou R, Qiu W, Huang N, Sun L, Li X, Bin J, Liao Y, Shi M, Liao W (2021) IOBR: multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures. Front Immun 12:687975

    Article  CAS  Google Scholar 

  • Zhu Q, McLellan JS, Kallewaard NL, Ulbrandt ND, Palaszynski S, Zhang J, Moldt B, Khan A, Svabek C, McAuliffe JM, Wrapp D, Patel NK, Cook KE, Richter BWM, Ryan PC, Yuan AQ, Suzich JA (2017) A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Sci Transl Med 9(388):e1928

    Article  Google Scholar 

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Funding

This work was supported by the Guangxi Natural Science Foundation (Grant No. 2020GXNSFDA238003).

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  1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China

    Lu Lin, Zenghua Liao & Chaoqian Li

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  1. Lu Lin
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  2. Zenghua Liao
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LL conceived and designed the study, analyzed the data, wrote the paper; ZL prepared the figures and/or tables; CL conceived and designed the study and reviewed the draft paper. All authors read and approved the final manuscript.

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Correspondence to Chaoqian Li.

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Lin, L., Liao, Z. & Li, C. Exploring Ribosomal Genes as Potential Biomarkers of the Immune Microenvironment in Respiratory Syncytial Virus Infection. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10778-6

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