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.
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
Karan A, Wadhera RK. Healthcare system stress due to Covid-19: evading an evolving crisis. J Hosp Med. 2021;16:127.
García LF. Immune response, inflammation, and the clinical spectrum of COVID-19, Front Immunol. 2020;11:1441.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Calder PC. Nutrition, immunity and COVID-19. BMJ Nutr Prev Health. 2020;3:74–92.
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.
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.
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.
Sambarey A, Prashanthi K, Chandra N. Mining large-scale response networks reveals ’topmost activities’ in Mycobacterium tuberculosis infection. Sci Rep. 2013;3:2302.
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.
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.
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.
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.
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.
Banerjee U, Baloni P, Singh A, Chandra N. Immune subtyping in latent tuberculosis. Front Immunol. 2021;12.
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.
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.
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.
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011;12:323.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Harding AT, Heaton NS. The impact of estrogens and their receptors on immunity and inflammation during infection. Cancers. 2022;14:909.
Taneja V. Sex hormones determine immune response. Front Immunol. 2018;9.
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.
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.
Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell. 2021;184:861–80.
Alqutami F, Senok A, Hachim M. COVID-19 transcriptomic atlas: a comprehensive analysis of COVID-19 related transcriptomics datasets. Front Genet. 2021;12.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Zietz M, Zucker J, Tatonetti NP. Associations between blood type and COVID-19 infection, intubation, and death. Nat Commun. 2020;11:5761.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
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
Ethics declarations
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.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41435-023-00210-1
- Springer Nature Limited