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Systems-level profiling of early peripheral host-response landscape variations across COVID-19 severity states in an Indian cohort

Genes & Immunity volume 24, pages 183–193 (2023)Cite this article

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Abstract

Host immune response to COVID-19 plays a significant role in regulating disease severity. Although big data analysis has provided significant insights into the host biology of COVID-19 across the world, very few such studies have been performed in the Indian population. This study utilizes a transcriptome-integrated network analysis approach to compare the immune responses between asymptomatic or mild and moderate-severe COVID-19 patients in an Indian cohort. An immune suppression phenotype is observed in the early stages of moderate-severe COVID-19 manifestation. A number of pathways are identified that play crucial roles in the host control of the disease such as the type I interferon response and classical complement pathway which show different activity levels across the severity spectrum. This study also identifies two transcription factors, IRF7 and ESR1, to be important in regulating the severity of COVID-19. Overall this study provides a deep understanding of the peripheral immune landscape in the COVID-19 severity spectrum in the Indian genetic background and opens up future research avenues to compare immune responses across global populations.

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Fig. 1: Generation of Indian cohort of COVID-19 patients.
Fig. 2: Gene expression profile in COVID-19 patients in comparison to healthy individuals.
Fig. 3: Pathway overrepresentation analysis of COVID-19 severity networks.
Fig. 4: Pathway status of type I interferon and complement pathway.
Fig. 5: Pathway status of carbonic anhydrase activity and ribosome biogenesis.
Fig. 6: Roles of IRF7 and ESR1 genes in COVID-19.
Fig. 7: Immune response and pathway activation model in COVID-19 across severity spectrum.

Data availability

The transcriptome data used in this study are available in GEO under ID GSE196822.

Code availability

All codes for Response Network Analysis have been previously made publicly available in the repository with Banerjee et al. [23].

References

  1. Karan A, Wadhera RK. Healthcare system stress due to Covid-19: evading an evolving crisis. J Hosp Med. 2021;16:127.

    Article  PubMed  PubMed Central  Google Scholar 

  2. García LF. Immune response, inflammation, and the clinical spectrum of COVID-19, Front Immunol. 2020;11:1441.

  3. Kwok KO, Huang Y, Tsoi MTF, Tang A, Wong SYS, Wei WI, et al. Epidemiology, clinical spectrum, viral kinetics and impact of COVID-19 in the Asia-Pacific region. Respirology. 2021;26:322–33. https://onlinelibrary.wiley.com/doi/pdf/10.1111/resp.14026.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kim D, Lee J-Y, Yang J-S, Kim JW, Kim VN, Chang H. The architecture of SARS-CoV-2 transcriptome. Cell. 2020;181:914–21.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guan W-J, Liang W-H, Zhao Y, Liang H-R, Chen Z-S, Li Y-M, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J. 2020;55:2000547.

  6. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arunachalam PS, Wimmers F, Mok CKP, Perera RAPM, Scott M, Hagan T, et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science. 2020;369:1210–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LEP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol. 2020;20:363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mehta P, Porter JC, Manson JJ, Isaacs JD, Openshaw PJM, McInnes IB, et al. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med. 2020;8:822–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tahaghoghi-Hajghorbani S, Zafari P, Masoumi E, Rajabinejad M, Jafari-Shakib R, Hasani B, et al. The role of dysregulated immune responses in COVID-19 pathogenesis. Virus Res. 2020;290:198197.

    Article  CAS  PubMed  Google Scholar 

  11. Kuri-Cervantes L, Pampena MB, Meng W, Rosenfeld AM, Ittner CAG, Weisman AR, et al. Comprehensive mapping of immune perturbations associated with severe COVID-19. Sci Immunol. 2020;5:eabd7114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Osuchowski MF, Winkler MS, Skirecki T, Cajander S, Shankar-Hari M, Lachmann G, et al. The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity. Lancet Respir Med. 2021;9:622–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Calder PC. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health. 2020;3:74–92.

  14. Velavan TP, Pallerla SR, Rüter J, Augustin Y, Kremsner PG, Krishna S, et al. Host genetic factors determining COVID-19 susceptibility and severity. eBioMedicine. 2021;72:103629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Song J-W, Lam SM, Fan X, Cao W-J, Wang S-Y, Tian H, et al. Omics-driven systems interrogation of metabolic dysregulation in COVID-19 pathogenesis. Cell Metab. 2020;32:188–202.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu P, Chen D, Ding W, Wu P, Hou H, Bai Y, et al. The trans-omics landscape of COVID-19. Nat Commun. 2021;12:4543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sambarey A, Prashanthi K, Chandra N. Mining large-scale response networks reveals ’topmost activities’ in Mycobacterium tuberculosis infection. Sci Rep. 2013;3:2302.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sambarey A, Devaprasad A, Baloni P, Mishra M, Mohan A, Tyagi P, et al. Meta-analysis of host response networks identifies a common core in tuberculosis. NPJ Syst Biol Appl. 2017;3:4.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bhosle A, Datey A, Chandrasekharan G, Singh D, Chakravortty D, Chandra N. A strategic target rescues trimethoprim sensitivity in Escherichia coli. iScience. 2020;23:100986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Metri R, Mohan A, Nsengimana J, Pozniak J, Molina-Paris C, Newton-Bishop J, et al. Identification of a gene signature for discriminating metastatic from primary melanoma using a molecular interaction network approach. Sci Rep. 2017;7:17314.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mishra S, Shukla P, Bhaskar A, Anand K, Baloni P, Jha RK, et al. Efficacy of -lactam/-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis. eLife. 2017;6:e25624.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ravichandran S, Banerjee U, Dr GD, Kandukuru R, Thakur C, Chakravortty D, et al. VB10, a new blood biomarker for differential diagnosis and recovery monitoring of acute viral and bacterial infections. EBioMedicine. 2021;67:103352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Banerjee U, Baloni P, Singh A, Chandra N. Immune subtyping in latent tuberculosis. Front Immunol. 2021;12.

  24. Banerjee U, Sankar S, Singh A, Chandra N. A multi-pronged computational pipeline for prioritizing drug target strategies for latent tuberculosis. Front Chem. 2020;8.

  25. Ravichandran S, Chandra N. Interrogation of genome-wide networks in biology: comparison of knowledge-based and statistical methods. Int J Adv in Eng Sci and Appl Math. 2019;11:119–37.

    Article  Google Scholar 

  26. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  27. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, et al. Orchestrating high-throughput genomic analysis with bioconductor. Nat Methods. 2015;12:115–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Banerjee U, Rao P, Reddy M, Hussain M, Chunchanur S, Ambica R, et al. A 9-gene biomarker panel identifies bacterial coinfections in culture-negative Covid-19 cases. Mol Omics. 2022;18:814–20.

    Article  CAS  PubMed  Google Scholar 

  31. Sambaturu N, Pusadkar V, Hannenhalli S, Chandra N. PathExt: a general framework for path-based mining of omics-integrated biological networks. Bioinformatics. 2021;37:1254–62.

    Article  CAS  PubMed  Google Scholar 

  32. McClain MT, Constantine FJ, Henao R, Liu Y, Tsalik EL, Burke TW, et al. Dysregulated transcriptional responses to SARS-CoV-2 in the periphery. Nat Commun. 2021;12:1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Georg P, Astaburuaga-Garc´ıa R, Bonaguro L, Brumhard S, Michalick L, Lippert LJ, et al. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell. 2022;185:493–512.e25.

    Article  CAS  PubMed  Google Scholar 

  34. Liu C-G, Zhang L, Jiang Y, Chatterjee D, Croce CM, Huebner K, et al. Modulation of gene expression in precancerous rat esophagus by dietary zinc deficit and replenishment. Cancer Res. 2005;65:7790–9.

    Article  CAS  PubMed  Google Scholar 

  35. Dong H-J, Zhang R, Kuang Y, Wang X-J. Selective regulation in ribosome biogenesis and protein production for efficient viral translation. Arch Microbiol. 2021;203:1021–32.

    Article  CAS  PubMed  Google Scholar 

  36. Simonin D, Diaz J-J, Mass'e T, Madjar J-J. Persistence of ribosomal protein synthesis after infection of HeLa cells by herpes simplex virus type 1. J Gen Virol. 1997;78:435–43.

    Article  CAS  PubMed  Google Scholar 

  37. Feng Q, Li L, Wang X. Identifying pathways and networks associated with the SARS-CoV-2 cell receptor ACE2 based on gene expression profiles in normal and SARS-CoV-2-infected human tissues. Front Mol Biosci. 2020;7.

  38. Harding AT, Heaton NS. The impact of estrogens and their receptors on immunity and inflammation during infection. Cancers. 2022;14:909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taneja V. Sex hormones determine immune response. Front Immunol. 2018;9.

  40. Sharp GC, Fraser A, Sawyer G, Kountourides G, Easey KE, Ford G, et al. The COVID-19 pandemic and the menstrual cycle: research gaps and opportunities. Int J Epidemiol. 2021;51:dyab239.

    Google Scholar 

  41. Edelman A, Boniface ER, Benhar E, Han L, Matteson KA, Favaro C, et al. Association between menstrual cycle length and coronavirus disease 2019 (COVID-19) vaccination: a U.S. Cohort, Obstetrics & Gynecology. 2022. https://doi.org/10.1097/AOG.0000000000004695.

  42. Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021;184:861–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Alqutami F, Senok A, Hachim M. COVID-19 transcriptomic atlas: a comprehensive analysis of COVID-19 related transcriptomics datasets. Front Genet. 2021;12.

  44. Islam ABMMK, Khan MA-A-K, Ahmed R, Hossain MS, Kabir SMT, Islam MS, et al. Transcriptome of nasopharyngeal samples from COVID-19 patients and a comparative analysis with other SARS-CoV-2 infection models reveal disparate host responses against SARS-CoV-2. J Transl Med. 2021;19:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kaur S, Singh A, Kaur J, Verma N, Pandey AK, Das S, et al. Upregulation of cytokine signalling in platelets increases risk of thrombophilia in severe COVID-19 patients. Blood Cells Mol Dis. 2022;94:102653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Singh NK, Srivastava S, Zaveri L, Bingi TC, Mesipogu R, Kumar V S, et al. Host transcriptional response to SARS-CoV-2 infection in COVID-19 patients. Clin Transl Med. 2021;11:e534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Migliorini F, Torsiello E, Spiezia F, Oliva F, Tingart M, Maffulli N. Association between HLA genotypes and COVID-19 susceptibility, severity and progression: a comprehensive review of the literature. Eur J Med Res. 2021;26:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tavasolian F, Rashidi M, Hatam GR, Jeddi M, Hosseini AZ, Mosawi SH, et al. HLA, immune response, and susceptibility to COVID-19. Front Immunol. 2021;11.

  49. Thorne LG, Bouhaddou M, Reuschl A-K, Zuliani-Alvarez L, Polacco B, Pelin A, et al. Evolution of enhanced innate immune evasion by SARS-CoV-2. Nature. 2022;602:487–95.

    Article  CAS  PubMed  Google Scholar 

  50. Tian W, Zhang N, Jin R, Feng Y, Wang S, Gao S, et al. Immune suppression in the early stage of COVID-19 disease. Nat Commun. 2020;11:5859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369:718–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science. 2020;370:eabd4570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Masood KI, Yameen M, Ashraf J, Shahid S, Mahmood SF, Nasir A, et al. Upregulated type I interferon responses in asymptomatic COVID-19 infection are associated with improved clinical outcome. Sci Rep. 2021;11:22958.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mu˜niz-Diaz E, Llopis J, Parra R, Roig I, Ferrer G, Grifols J, et al. Relationship between the ABO blood group and COVID-19 susceptibility, severity and mortality in two cohorts of patients. Blood Transfus. 2021;19:54–63.

    PubMed  Google Scholar 

  55. Zietz M, Zucker J, Tatonetti NP. Associations between blood type and COVID-19 infection, intubation, and death. Nat Commun. 2020;11:5761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Guillon P, Cl´ement M, S´ebille V, Rivain J-G, Chou C-F, Ruvo¨en-Clouet N, et al. Inhibition of the interaction between the SARS-CoV Spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology. 2008;18:1085–93.

    Article  CAS  PubMed  Google Scholar 

  57. Schubert K, Karousis ED, Jomaa A, Scaiola A, Echeverria B, Gurzeler L-A, et al. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat Struct Mol Biol. 2020;27:959–66.

    Article  CAS  PubMed  Google Scholar 

  58. Liu Y, Yan L-M, Wan L, Xiang T-X, Le A, Liu J-M, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020;20:656–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hue S, Beldi-Ferchiou A, Bendib I, Surenaud M, Fourati S, Frapard T, et al. Uncontrolled innate and impaired adaptive immune responses in patients with COVID-19 acute respiratory distress syndrome. Am J Respir Crit Care Med. 2020;202:1509–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Astbury S, Reynolds CJ, Butler DK, Mu˜noz-Sandoval DC, Lin K-M, Pieper FP, et al. HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19. Immunology. 2022;166:68–77. https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.13450.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Department of Biotechnology, Government of India and the Indian Institute of Science are acknowledged for providing the funding for this study in the form of a DBT-IISc partnership grant and Institute Research Support Grant, respectively. Biokart India Pvt Ltd is acknowledged for their support in executing high-throughput sequencing.

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Authors and Affiliations

  1. Department of Biochemistry, Indian Institute of Science, Bengaluru, India

    Ushashi Banerjee & Nagasuma Chandra

  2. Bangalore Medical College and Research Institute (BMCRI), Bengaluru, India

    Sneha Chunchanur & Ambica R

  3. Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, India

    Kithiganahalli Narayanaswamy Balaji, Amit Singh & Dipshikha Chakravortty

  4. Center for Infectious Disease Research, Indian Institute of Science, Bengaluru, India

    Amit Singh & Dipshikha Chakravortty

  5. Center for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru, India

    Nagasuma Chandra

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Contributions

NC conceptualized, designed, and supervised the study. UB performed methodology, analysis, and interpretation. SC and AR performed sample collection and classification. KNB, AS and DC provided supervision and critical insights. UB wrote the first draft of manuscript. All authors revised and approved the submitted manuscript.

Corresponding author

Correspondence to Nagasuma Chandra.

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Competing interests

NC is a co-founder of the companies qBiome Research Pvt Ltd and HealSeq Precision Medicine Pvt Ltd. They had no role in this manuscript. The remaining authors declare no conflict of interest.

Ethical approval

Ethical approval for this study was obtained from the Institutional Human Ethics Committee at Bangalore Medical College and Research Institute, Bangalore, India (BMCRI/PS/02/2021-21), and IISc (1-26062020), Bangalore, India. Informed consent was obtained from all the participants prior to recruitment to the study.

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Banerjee, U., Chunchanur, S., R, A. et al. Systems-level profiling of early peripheral host-response landscape variations across COVID-19 severity states in an Indian cohort. Genes Immun 24, 183–193 (2023). https://doi.org/10.1038/s41435-023-00210-1

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