Unraveling Metagenomics: A Comprehensive Diagnostic Approach for COVID-19

Year : 2024 | Volume :01 | Issue : 02 | Page : 19-28

Lavanya T. Nair

Shweta Singh


The COVID-19 pandemic has brought attention to the need for rapid, accurate, and scalable diagnostic techniques. Metagenomics, a powerful technique that enables the comprehensive analysis of genetic material from complex microbial communities, has emerged as a promising diagnostic approach for COVID-19. This article elucidates the principles of metagenomic sequencing, highlighting its ability to detect viral RNA directly from clinical samples without prior knowledge of the pathogen. Furthermore, we discuss the advantages of metagenomics over traditional diagnostic methods, including its ability to identify emerging viral variants and co-infections. Additionally, we explore the challenges and limitations associated with metagenomic diagnostics, such as bioinformatics complexity and cost considerations. Moreover, we review recent advancements in metagenomic technologies and their applications in COVID-19 surveillance, outbreak monitoring, and vaccine development. Finally, we discuss future perspectives and the potential integration of metagenomics into routine clinical practice, emphasizing its role in shaping the future of infectious disease diagnosis and management.

Keywords: Metagenomics, COVID-19 diagnostics, viral variants, bioinformatics, surveillance

[This article belongs to International Journal of Tropical Medicines(ijtm)]

How to cite this article: Lavanya T. Nair, Shweta Singh. Unraveling Metagenomics: A Comprehensive Diagnostic Approach for COVID-19. International Journal of Tropical Medicines. 2024; 01(02):19-28.
How to cite this URL: Lavanya T. Nair, Shweta Singh. Unraveling Metagenomics: A Comprehensive Diagnostic Approach for COVID-19. International Journal of Tropical Medicines. 2024; 01(02):19-28. Available from: https://journals.stmjournals.com/ijtm/article=2024/view=145266


  1. Hugenholtz, P., & Tyson, G. W. (2008). Microbiology: metagenomics. Nature, 455, 481–483. doi:10.1038/455481
  2. Passaro, N., Casagrande, A., Chiara, M., Fosso, B., Manzari, C., D’Erchia, A. M., … Crescenzi, M. (2019). No metagenomic evidence of tumorigenic viruses in cancers from a selected cohort of immunosuppressed subjects. Scientific Reports, 9(1), 19815. doi:10.1038/s41598-019-56240-1
  3. Heba, H. (2020). Metagenomic Next-Generation Sequencing of Nasopharyngeal Specimens Collected from Confirmed and Suspect COVID-19 Patients. 11. doi:10.1128/mBio.01969-20
  4. Mokili, J. L. (2012). Metagenomics and future perspectives in virus discovery. Current Opinion in Virology, 2, 63–77. doi: 10.1016/j.coviro.2011.12.004
  5. Research Council (US) Committee on Metagenomics: Challenges and Functional Applications. The New Science of Metagenomics: Revealing the Secrets of Our Microbial Planet. (2007). doi:10.17226/11902
  6. Simner, P. J. (2018). Understanding the Promises and Hurdles of Metagenomic Next-Generation Sequencing as a Diagnostic Tool for Infectious Diseases. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 66, 778–788. doi:10.1093/cid/cix881
  7. Herbert, W., & Todd, J. A. (2011). Metagenomics and personalized medicine. Cell, 147, 44–56. doi: 10.1016/j.cell.2011.09.009
  8. Chiu, C., & Miller, S. A. (2019). Clinical metagenomics. Nature Reviews. Genetics, 20, 341–355. doi:10.1038/s41576-019-0113-7
  9. Ma, S., Zhang, F., Zhou, F., Li, H., Ge, W., Gan, R., … Huang, Z. (2021). Metagenomic analysis reveals oropharyngeal microbiota alterations in patients with COVID-19. Signal Transduction and Targeted Therapy, 6(1), 191. doi:10.1038/s41392-021-00614-3
  10. Edwards, R. A., & Rohwer, F. (2005). Viral metagenomics. Nature Reviews. Microbiology, 3, 504–510. doi:10.1038/nrmicro1163
  11. Carbo, E. C., Sidorov, I. A., Zevenhoven-Dobbe, J. C., Snijder, E. J., Claas, E. C., Laros, J. F. J., … de Vries, J. J. C. (2020). Coronavirus discovery by metagenomic sequencing: a tool for pandemic preparedness. Journal of Clinical Virology: The Official Publication of the Pan American Society for Clinical Virology, 131(104594), 104594. doi:10.1016/j.jcv.2020.104594
  12. Garrido-Cardenas, J. A., & Manzano-Agugliaro, F. (2017). The metagenomics worldwide research. Current Genetics, 63(5), 819–829. doi:10.1007/s00294-017-0693-8
  13. Johnson, B. A., Graham, R. L., & Menachery, V. D. (2018). Viral metagenomics, protein structure, and reverse genetics: Key strategies for investigating coronaviruses. Virology, 517, 30–37. doi:10.1016/j.virol.2017.12.009
  14. Deng, X., Achari, A., Federman, S., Yu, G., Somasekar, S., Bártolo, I., … Chiu, C. Y. (2020). Metagenomic sequencing with spiked primer enrichment for viral diagnostics and genomic surveillance. Nature Microbiology, 5(3), 443–454. doi:10.1038/s41564-019-0637-9
  15. Wooley, J. C., & Ye, Y. (2009). Metagenomics: Facts and artifacts, and computational challenges. Journal of Computer Science and Technology, 25(1), 71–81. doi:10.1007/s11390-010-9306-4
  16. Sawyer, A., Free, T., & Martin, J. (2021). Metagenomics: preventing future pandemics. BioTechniques, 70(1), 1–4. doi:10.2144/btn-2020-0166
  17. Babiker, A., Bradley, H. L., Stittleburg, V. D., Ingersoll, J. M., Key, A., Kraft, C. S., … Piantadosi, A. (2020). Metagenomic sequencing to detect respiratory viruses in persons under investigation for COVID-19. Journal of Clinical Microbiology, 59(1), e02142-20. doi:10.1128/JCM.02142-20
  18. Dávila-Ramos, S., Castelán-Sánchez, H. G., Martínez-Ávila, L., Sánchez-Carbente, M. D. R., Peralta, R., Hernández-Mendoza, A., … Batista-García, R. A. (2019). A review on viral metagenomics in extreme environments. Frontiers in Microbiology, 10, 2403. doi:10.3389/fmicb.2019.02403
  19. Nooij, S., Schmitz, D., Vennema, H., Kroneman, A., & Koopmans, M. P. G. (2018). Overview of virus metagenomic classification methods and their biological applications. Frontiers in Microbiology, 9, 749. doi:10.3389/fmicb.2018.00749
  20. Liu, B., Shao, N., Wang, J., Zhou, S., Su, H., Dong, J., … Yang, F. (2020). An optimized metagenomic approach for virome detection of clinical pharyngeal samples with respiratory infection. Frontiers in Microbiology, 11, 1552. doi:10.3389/fmicb.2020.01552
  21. Li, N., Cai, Q., Miao, Q., Song, Z., Fang, Y., & Hu, B. (2021). High-throughput metagenomics for identification of pathogens in the clinical settings. Small Methods, 5(1), 2000792. doi:10.1002/smtd.202000792
  22. Han, D. (2019). “mNGS in clinical microbiology laboratories: on the road to maturity. Critical Reviews in Microbiology, 45, 668–685. doi:10.1080/1040841X.2019.1681933
  23. Duan, H. (2021). The diagnostic value of metagenomic next•generation sequencing in infectious diseases. BMC Infectious Diseases, 21. doi:10.1186/s12879-020-05746-5
  24. Tasha, M., & Hollister, E. B. (2020). Potential Applications of Human Viral Metagenomics and Reference Materials: Considerations for Current and Future Viruses. Applied and Environmental Microbiology, 86, e01794-1814. doi:10.1128/AEM.01794-20
  25. Fulci, V., Carissimi, C., & Laudadio, I. (2021). COVID-19 and preparing for future ecological crises: Hopes from metagenomics in facing current and future viral pandemic challenges. Omics: A Journal of Integrative Biology, 25(6), 336–341. doi:10.1089/omi.2021.0058
  26. Mohamadian, M., Chiti, H., Shoghli, A., Biglari, S., Parsamanesh, N., & Esmaeilzadeh, A. (2021). COVID-19: Virology, biology and novel laboratory diagnosis. The Journal of Gene Medicine, 23(2), e3303. doi:10.1002/jgm.3303
  27. Escobar-Zepeda, A., Vera-Ponce de León, A., & Sanchez-Flores, A. (2015). The road to metagenomics: From microbiology to DNA sequencing technologies and bioinformatics. Frontiers in Genetics, 6, 348. doi:10.3389/fgene.2015.00348
  28. Sehli, S., Allali, I., Chahboune, R., Bakri, Y., Al Idrissi, N., Hamdi, S., … Ghazal, H. (2021). Metagenomics approaches to investigate the gut microbiome of COVID-19 patients. Bioinformatics and Biology Insights, 15, 1177932221999428. doi:10.1177/1177932221999428
  29. Miao, Q., Ma, Y., Ling, Y., Jin, W., Su, Y., Wang, Q., … Hu, B. (2021). Evaluation of superinfection, antimicrobial usage, and airway microbiome with metagenomic sequencing in COVID-19 patients: A cohort study in Shanghai. Wei Mian Yu Gan Ran Za Zhi [Journal of Microbiology, Immunology, and Infection], 54(5), 808–815. doi:10.1016/j.jmii.2021.03.015
  30. Consider something viral in your search. (2011). Nature Reviews. Microbiology, 9, 308–309. doi:10.1038/nrmicro2563
  31. Xie, F. (2021). Clinical metagenomics assessments improve diagnosis and outcomes in community-acquired pneumonia. BMC Infectious Diseases, 21. doi:10.1186/s12879-021-06039-1
  32. Li, H. (2018). Detection of Pulmonary Infectious Pathogens From Lung Biopsy Tissues by Metagenomic Next-Generation Sequencing. Frontiers in Cellular and Infection Microbiology, 8. doi:10.3389/fcimb.2018.00205
  33. Riesenfeld, C. S. (2004). Metagenomics: genomic analysis of microbial communities. Annual Review of Genetics, 38, 525–552. doi:10.1146/annurev.genet.38.072902.091216
  34. Schloss, P. D., & Handelsman, J. (2003). Biotechnological prospects from metagenomics. Current Opinion in Biotechnology, 14, 303–310. doi:10.1016/s0958-1669(03)00067-3
  35. Streit, W. R., & Schmitz, R. A. (2004). Metagenomics–the key to the uncultured microbes. Current Opinion in Microbiology, 7(5), 492–498. doi:10.1016/j.mib.2004.08.002
  36. Forbes, J. D. (2017). Metagenomics: The Next Culture-Independent Game Changer. Frontiers in Microbiology, 8. doi:10.3389/fmicb.2017.01069
  37. Gu, W. (2021). Rapid pathogen detection by metagenomic next-generation sequencing of infected body fluids. Nature Medicine Vol, 27, 115–124. doi:10.1038/s41591-020-1105-z
  38. Zhu, N. (2019). A Novel Coronavirus from Patients with Pneumonia in China. The New England Journal of Medicine, 382, 727–733. doi:10.1056/NEJMoa2001017
  39. Chen, N. (2020). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 395, 507–513. doi:10.1016/S0140-6736(20)30211-7
  40. Li, N. (2019). The Commensal Microbiota and Viral Infection: A Comprehensive Review. Frontiers in Immunology, 10. doi:10.3389/fimmu.2019.01551
  41. Deng, Z., & Delwart, E. (2021). ContigExtender: a new approach to improving de novo sequence assembly for viral metagenomics data. BMC Bioinformatics, 22(1), 119. doi:10.1186/s12859-021-04038-2
  42. Ke, S., Weiss, S. T., & Liu, Y.-Y. (2022). Dissecting the role of the human microbiome in COVID-19 via metagenome-assembled genomes. Nature Communications, 13(1), 5235. doi:10.1038/s41467-022-32991-w
  43. Hu, T., Chitnis, N., Monos, D., & Dinh, A. (2021). Next-generation sequencing technologies: An overview. Human Immunology, 82(11), 801–811. doi:10.1016/j.humimm.2021.02.012
  44. Bhoyar, R. C., Jain, A., Sehgal, P., Divakar, M. K., Sharma, D., Imran, M., … Sivasubbu, S. (2021). High throughput detection and genetic epidemiology of SARS-CoV-2 using COVIDSeq next-generation sequencing. PloS One, 16(2), e0247115. doi:10.1371/journal.pone.0247115
  45. Chiara, M., D’Erchia, A. M., Gissi, C., Manzari, C., Parisi, A., Resta, N., … Pesole, G. (2021). Next generation sequencing of SARS-CoV-2 genomes: challenges, applications and opportunities. Briefings in Bioinformatics, 22(2), 616–630. doi:10.1093/bib/bbaa297
  46. Gu, W., Miller, S., & Chiu, C. Y. (2019). Clinical metagenomic next-generation sequencing for pathogen detection. Annual Review of Pathology, 14(1), 319–338. doi:10.1146/annurev-pathmechdis-012418-012751
  47. Babiker, A., Bradley, H., Stittleburg, V., Key, A., Kraft, C. S., Waggoner, J., & Piantadosi, A. (2020). Metagenomic sequencing to detect respiratory viruses in persons under investigation for COVID-19. medRxiv: The Preprint Server for Health Sciences. doi:10.1101/2020.09.09.20178764
  48. Sanders, M., Kiem, I., & Lagunoff, D. (1953). Cultivation of Viruses. A Critical Review. Arch. Pathol, 56(2), 148–225.
  49. Ren, J., Song, K., Deng, C., Ahlgren, N. A., Fuhrman, J. A., Li, Y., … Sun, F. (2020). Identifying viruses from metagenomic data using deep learning. Quantitative Biology (Beijing, China), 8(1), 64–77. doi:10.1007/s40484-019-0187-4
  50. Aljabr, W., Dandachi, I., Abbas, B., Karkashan, A., Al-Amari, A., & Alshahrani, D. (2024). Metagenomic next-generation sequencing of nasopharyngeal microbiota in COVID-19 patients with different disease severities. Microbiology Spectrum, e04166-4189.

Regular Issue Subscription Review Article
Volume 01
Issue 02
Received April 4, 2024
Accepted April 16, 2024
Published May 7, 2024