Abstract
SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination. The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences. Molecular markers for evaluating the pathogenicity of new variants are therefore needed. By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels, six key molecules on the polyamine biosynthesis pathway including putrescine, SAM, dc-SAM, ODC1, SAMS, and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants. To validate our discovery, human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients. Using ODC1 as a proof-of-concept, differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system (RAS) and positively associated with ACE2 activity. Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern (VOCs) and was found to be correlated with each VOCs’ pathogenic properties. Particularly, the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models. Our work, therefore, presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability statement
All data reported In this paper will be available by the corresponding author upon request.
References
Adebayo, A., Varzideh, F., Wilson, S., Gambardella, J., Eacobacci, M., Jankauskas, S.S., Donkor, K., Kansakar, U., Trimarco, V., Mone, P., et al. (2021). l-Arginine and COVID-19: an update. Nutrients 13, 3951.
Amoutzias, G.D., Nikolaidis, M., Tryfonopoulou, E., Chlichlia, K., Markoulatos, P., and Oliver, S.G. (2022). The remarkable evolutionary plasticity of coronaviruses by mutation and recombination: insights for the COVID-19 pandemic and the future evolutionary paths of SARS-CoV-2. Viruses 14, 78.
Arora, P., Kempf, A., Nehlmeier, I., Schulz, S.R., Cossmann, A., Stankov, M.V., Jäck, H.M., Behrens, G.M.N., Pöhlmann, S., and Hoffmann, M. (2022). Augmented neutralisation resistance of emerging omicron subvariants BA.2.12.1, BA.4, and BA.5. Lancet Infect Dis 22, 1117–1118.
Asosingh, K., Lauruschkat, C.D., Alemagno, M., Frimel, M., Wanner, N., Weiss, K., Kessler, S., Meyers, D.A., Bennett, C., Xu, W., et al. (2020). Arginine metabolic control of airway inflammation. JCI Insight 5.
Babbar, N., Murray-Stewart, T., and Casero, R.A. (2007). Inflammation and polyamine catabolism: the good, the bad and the ugly. Biochem Soc Trans 35, 300–304.
Bao, J., Sun, R., Ai, J., Qian, L., Liu, F., Wang, H., Tan, L., Cai, X., Shi, Y., Liang, X., et al. (2022). Proteomic characterization of Omicron SARS-CoV-2 host response. Cell Discov 8, 46.
Bernardes, J.P., Mishra, N., Tran, F., Bahmer, T., Best, L., Blase, J.I., Bordoni, D., Franzenburg, J., Geisen, U., Josephs-Spaulding, J., et al. (2020). Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19. Immunity 53, 1296–1314.e9.
Cao, G., Song, Z., Hong, Y., Yang, Z., Song, Y., Chen, Z., Chen, Z., and Cai, Z. (2020). Large-scale targeted metabolomics method for metabolite profiling of human samples. Anal Chim Acta 1125, 144–151.
Chiu, M.C., Li, C., Liu, X., Yu, Y., Huang, J., Wan, Z., Xiao, D., Chu, H., Cai, J.P., Zhou, B., et al. (2022). A bipotential organoid model of respiratory epithelium recapitulates high infectivity of SARS-CoV-2 Omicron variant. Cell Discov 8, 57.
Chu, H., Hou, Y., Yang, D., Wen, L., Shuai, H., Yoon, C., Shi, J., Chai, Y., Yuen, T.T.T., Hu, B., et al. (2022). Coronaviruses exploit a host cysteine-aspartic protease for replication. Nature 609, 785–792.
and Clevers, H. (2020). COVID-19: organoids go viral. Nat Rev Mol Cell Biol 21, 355–356.
Cui, L., Nithipatikom, K., and Campbell, W.B. (2007). Simultaneous analysis of angiotensin peptides by LC-MS and LC-MS/MS: Metabolism by bovine adrenal endothelial cells. Anal Biochem 369, 27–33.
Del Valle, D.M., Kim-Schulze, S., Huang, H.H., Beckmann, N.D., Nirenberg, S., Wang, B., Lavin, Y., Swartz, T.H., Madduri, D., Stock, A., et al. (2020). An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med 26, 1636–1643.
Duvvuri, V.R., Baumgartner, A., Molani, S., Hernandez, P.V., Yuan, D., Roper, R.T., Matos, W.F., Robinson, M., Su, Y., Subramanian, N., et al. (2022). Angiotensin-converting enzyme (ACE) inhibitors may moderate COVID-19 hyperinflammatory response: an observational study with deep immunophenotyping. Health Data Sci 2022.
Firpo, M.R., Mastrodomenico, V., Hawkins, G.M., Prot, M., Levillayer, L., Gallagher, T., Simon-Loriere, E., and Mounce, B.C. (2021). Targeting polyamines inhibits coronavirus infection by reducing cellular attachment and entry. ACS Infect Dis 7, 1423–1432.
Gassen, N.C., Papies, J., Bajaj, T., Emanuel, J., Dethloff, F., Chua, R.L., Trimpert, J., Heinemann, N., Niemeyer, C., Weege, F., et al. (2021). SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals. Nat Commun 12, 3818.
Gheblawi, M., Wang, K., Viveiros, A., Nguyen, Q., Zhong, J.C., Turner, A.J., Raizada, M.K., Grant, M.B., and Oudit, G.Y. (2020). Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 126, 1456–1474.
Halfmann, P.J., Iida, S., Iwatsuki-Horimoto, K., Maemura, T., Kiso, M., Scheaffer, S.M., Darling, T.L., Joshi, A., Loeber, S., Singh, G., et al. (2022). SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters. Nature 603, 687–692.
Han, Y., Yang, L., Lacko, L.A., and Chen, S. (2022). Human organoid models to study SARS-CoV-2 infection. Nat Methods 19, 418–428.
Harvey, W.T., Carabelli, A.M., Jackson, B., Gupta, R.K., Thomson, E.C., Harrison, E. M., Ludden, C., Reeve, R., Rambaut, A., Peacock, S.J., et al. (2021). SARS-CoV-2 variants, spike mutations and immune escape. Nat Rev Microbiol 19, 409–424.
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., et al. (2020a). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8.
Hoffmann, M., Kleine-Weber, H., and Pöhlmann, S. (2020b). A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell 78, 779–784.e5.
Hughes, C.S., Moggridge, S., Müller, T., Sorensen, P.H., Morin, G.B., and Krijgsveld, J. (2019). Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat Protoc 14, 68–85.
Jones, S.A., and Hunter, C.A. (2021). Is IL-6 a key cytokine target for therapy in COVID-19? Nat Rev Immunol 21, 337–339.
Kim, S., Kawamura, M., Wanibuchi, H., Ohta, K., Hamaguchi, A., Omura, T., Yukimura, T., Miura, K., and Iwao, H. (1995). Angiotensin II type 1 receptor blockade inhibits the expression of immediate-early genes and fibronectin in rat injured artery. Circulation 92, 88–95.
Lau, S.Y., Wang, P., Mok, B.W.Y., Zhang, A.J., Chu, H., Lee, A.C.Y., Deng, S., Chen, P., Chan, K.H., Song, W., et al. (2020). Attenuated SARS-CoV-2 variants with deletions at the S1/S2 junction. Emerg Microbes Infect 9, 837–842.
Li, M.M.H., and MacDonald, M.R. (2016). Polyamines: small molecules with a big role in promoting virus infection. Cell Host Microbe 20, 123–124.
Li, Z., Peng, M., Chen, P., Liu, C., Hu, A., Zhang, Y., Peng, J., Liu, J., Li, Y., Li, W., et al. (2022). Imatinib and methazolamide ameliorate COVID-19-induced metabolic complications via elevating ACE2 enzymatic activity and inhibiting viral entry. Cell Metab 34, 424–440.e7.
Liu, S., Zhu, L., Xie, G., Mok, B.W.Y., Yang, Z., Deng, S., Lau, S.Y., Chen, P., Wang, P., Chen, H., et al. (2022). Potential antiviral target for SARS-CoV-2: a key early responsive kinase during viral entry. CCS Chem 4, 112–121.
Moolamalla, S.T.R., Balasubramanian, R., Chauhan, R., Priyakumar, U.D., and Vinod, P.K. (2021). Host metabolic reprogramming in response to SARS-CoV-2 infection: A systems biology approach. Microb Pathog 158, 105114.
Mounce, B.C., Olsen, M.E., Vignuzzi, M., and Connor, J.H. (2017). Polyamines and Their Role in Virus Infection. Microbiol Mol Biol Rev 81.
Nakayasu, E.S., Nicora, C.D., Sims, A.C., Burnum-Johnson, K.E., Kim, Y.M., Kyle, J.E., Matzke, M.M., Shukla, A.K., Chu, R.K., Schepmoes, A.A., et al. (2016). MPLEx: a robust and universal protocol for single-sample integrative proteomic, metabolomic, and lipidomic analyses. mSystems 1: e00043–16.
Rees, C.A., Rostad, C.A., Mantus, G., Anderson, E.J., Chahroudi, A., Jaggi, P., Wrammert, J., Ochoa, J.B., Ochoa, A., Basu, R.K., et al. (2021). Altered amino acid profile in patients with SARS-CoV-2 infection. Proc Natl Acad Sci USA 118, e2101708118.
Saito, K., Packianathan, S., and Longo, L.D. (1997). Free radical-induced elevation of ornithine decarboxylase activity in developing rat brain slices. Brain Res 763, 232–238.
Santos, R.A.S., Sampaio, W.O., Alzamora, A.C., Motta-Santos, D., Alenina, N., Bader, M., and Campagnole-Santos, M.J. (2018). The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol Rev 98, 505–553.
Shuai, H., Chan, J.F.W., Hu, B., Chai, Y., Yuen, T.T.T., Yin, F., Huang, X., Yoon, C., Hu, J.C., Liu, H., et al. (2022). Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron. Nature 603, 693–699.
Smirnova, O.A., Isaguliants, M.G., Hyvonen, M.T., Keinanen, T.A., Tunitskaya, V.L., Vepsalainen, J., Alhonen, L., Kochetkov, S.N., and Ivanov, A.V. (2012). Chemically induced oxidative stress increases polyamine levels by activating the transcription of ornithine decarboxylase and spermidine/spermine-N1-acetyltransferase in human hepatoma HUH7 cells. Biochimie 94, 1876–1883.
Stukalov, A., Girault, V., Grass, V., Karayel, O., Bergant, V., Urban, C., Haas, D.A., Huang, Y., Oubraham, L., Wang, A., et al. (2021). Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 594, 246–252.
Suzuki, R., Yamasoba, D., Kimura, I., Wang, L., Kishimoto, M., Ito, J., Morioka, Y., Nao, N., Nasser, H., Uriu, K., et al. (2022). Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. Nature 603, 700–705.
Tate, P.M., Mastrodomenico, V., and Mounce, B.C. (2019). Ribavirin induces polyamine depletion via nucleotide depletion to limit virus replication. Cell Rep 28, 2620–2633.e4.
Tegally, H., Moir, M., Everatt, J., Giovanetti, M., Scheepers, C., Wilkinson, E., Subramoney, K., Makatini, Z., Moyo, S., Amoako, D.G., et al. (2022). Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa. Nat Med 28, 1785–1790.
van Esch, J.H.M., Gembardt, F., Sterner-Kock, A., Heringer-Walther, S., Le, T.H., Lassner, D., Stijnen, T., Coffman, T.M., Schultheiss, H.P., Danser, A.H.J., et al. (2010). Cardiac phenotype and angiotensin II levels in AT1a, AT1b, and AT2 receptor single, double, and triple knockouts. Cardiovasc Res 86, 401–409.
Wang, P., Lau, S.Y., Deng, S., Chen, P., Mok, B.W.Y., Zhang, A.J., Lee, A.C.Y., Chan, K.H., Tam, R.C.Y., Xu, H., et al. (2021). Characterization of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein. Nat Commun 12, 2790.
Wang, T., Fan, S.P., and Chen, Y.G. (2023). Organoids: a new research model for SARS-CoV-2infection and treatment (in Chinese). Sci Sin Vitae 53, 238–249.
Xie, G., Zhu, L., Song, Y., Huang, W., Hu, D., and Cai, Z. (2021a). An integrated quantitative proteomics strategy reveals the dual mechanisms of celastrol against acute inflammation. Chin Chem Lett 32, 2164–2168.
Xie, G., Zhu, L., Zhang, Y., Song, Y., Zhang, H., Yang, Z., and Cai, Z. (2021b). Sulfinylation on superoxide dismutase 1 Cys111: novel mechanism for 1-nitropyrene to promote acute reactive oxygen species generation. Small Struct 2, 2000123.
Yuan, S., Ye, Z.W., Liang, R., Tang, K., Zhang, A.J., Lu, G., Ong, C.P., Man Poon, V.K., Chan, C.C.S., Mok, B.W.Y., et al. (2022). Pathogenicity, transmissibility, and fitness of SARS-CoV-2 Omicron in Syrian hamsters. Science 377, 428–433.
Zhang, C.S., Zhang, B., Li, M., Wei, X., Gong, K., Li, Z., Yao, X., Wu, J., Zhang, C., Zhu, M., et al. (2022a). Identification of serum metabolites enhancing inflammatory responses in COVID-19. Sci China Life Sci 65, 1971–1984.
Zhang, J., Walker, M.E., Sanidad, K.Z., Zhang, H., Liang, Y., Zhao, E., Chacon-Vargas, K., Yeliseyev, V., Parsonnet, J., Haggerty, T.D., et al. (2022b). Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Nat Commun 13, 136.
Zhou, J., Li, C., Sachs, N., Chiu, M.C., Wong, B.H.Y., Chu, H., Poon, V.K.M., Wang, D., Zhao, X., Wen, L., et al. (2018). Differentiated human airway organoids to assess infectivity of emerging influenza virus. Proc Natl Acad Sci USA 115, 6822–6827.
Zhu, L., Chen, H., and Cai, Z. (2022). Zoonotic attack: An underestimated threat of SARS-CoV-2? Innovation 3, 100242.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (21705137), the Theme-based Research Scheme (TRS, T11-709/21-N) and the Collaborative Research Fund (CRF, C7042-21G) of the Research Grants Council of the HKSAR government, and the Tier 1 Research Start-up Grants from Research Committee of Hong Kong Baptist University (162874).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
The author(s) declare that they have no conflict of interest.
Supporting Information
Rights and permissions
About this article
Cite this article
Xie, G., Zhu, L., Liu, S. et al. Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants. Sci. China Life Sci. 67, 83–95 (2024). https://doi.org/10.1007/s11427-022-2379-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-022-2379-x