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. 2022 Mar 10;65(9):1866–1880. doi: 10.1007/s11427-021-2070-y

A urinary proteomic landscape of COVID-19 progression identifies signaling pathways and therapeutic options

Yuntao Liu 1,7,#, Lan Song 2,#, Nairen Zheng 2,#, Jinwen Shi 2,#, Hongxing Wu 3, Xing Yang 3, Nianci Xue 1,2, Xing Chen 4, Yimin Li 5,6, Changqing Sun 8, Cha Chen 1, Lijuan Tang 1, Xiaotian Ni 3, Yi Wang 2, Yaling Shi 4,✉, Jianwen Guo 1,7,✉, Guangshun Wang 8,✉, Zhongde Zhang 1,7,✉, Jun Qin 2,✉
PMCID: PMC8922985  PMID: 35290573

Abstract

Signaling pathway alterations in COVID-19 of living humans as well as therapeutic targets of the host proteins are not clear. We analyzed 317 urine proteomes, including 86 COVID-19, 55 pneumonia and 176 healthy controls, and identified specific RNA virus detector protein DDX58/RIG-I only in COVID-19 samples. Comparison of the COVID-19 urinary proteomes with controls revealed major pathway alterations in immunity, metabolism and protein localization. Biomarkers that may stratify severe symptoms from moderate ones suggested that macrophage induced inflammation and thrombolysis may play a critical role in worsening the disease. Hyper activation of the TCA cycle is evident and a macrophage enriched enzyme CLYBL is up regulated in COVID-19 patients. As CLYBL converts the immune modulatory TCA cycle metabolite itaconate through the citramalyl-CoA intermediate to acetyl-CoA, an increase in CLYBL may lead to the depletion of itaconate, limiting its anti-inflammatory function. These observations suggest that supplementation of itaconate and inhibition of CLYBL are possible therapeutic options for treating COVID-19, opening an avenue of modulating host defense as a means of combating SARS-CoV-2 viruses.

Supporting Information

The supporting information is available online at 10.1007/s11427-021-2070-y. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

Keywords: COVID-19, urine, proteome, CLYBL, itaconate

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFA0505102, 2017YFA0505103, 2017YFA0505104, 2017YFC0908404, 2018YFA0507503, 2020YFA0708001), the National Natural Science Foundation of China (81874237, 31870828), Major National Science and technology projects (2017ZX10305501-006), National Administration of Traditional Chinese Medicine: 2019 Project of Building Evidence Based Practice Capacity for TCM (2019XZZX-LG003), Guangdong Key-Area Research and Development Program (2019B020229002, 2020B1111300005), Guangzhou Science and Technology Program (201902020009), and Guangdong Provincial Key Laboratory of Research on Emergency in TCM (2017B030314176).

Supporting Information

Appendix (1.9MB, pdf)
11427_2021_2070_MOESM2_ESM.xlsx (58.5KB, xlsx)

Supplementary material, approximately 58.4 KB.

11427_2021_2070_MOESM3_ESM.xlsx (5MB, xlsx)

Supplementary material, approximately 4.95 MB.

11427_2021_2070_MOESM4_ESM.xlsx (1.1MB, xlsx)

Supplementary material, approximately 1.12 MB.

11427_2021_2070_MOESM5_ESM.xlsx (282.5KB, xlsx)

Supplementary material, approximately 282 KB.

11427_2021_2070_MOESM6_ESM.xlsx (657.9KB, xlsx)

Supplementary material, approximately 657 KB.

Footnotes

Compliance and ethics

J.Q. is a cofounder and co-owner of the Beijing Pineal Health Management Co., Ltd. X.N., H.W., and X.Y. are employees of Beijing Pineal Health Management Co., Ltd. All other authors declare that they have no conflict of interest. All work performed in this study was approved by The Second Affiliated Hospital of Guangzhou University of Chinese Medicine Ethics Committee and written informed consents were obtained from patients.

Contributed equally to this work

Contributor Information

Yaling Shi, Email: gz8hsyl@126.com.

Jianwen Guo, Email: jianwen_guo@qq.com.

Guangshun Wang, Email: wgsTMUBH@163.com.

Zhongde Zhang, Email: Doctorzzd99@163.com.

Jun Qin, Email: jqin1965@126.com.

References

  1. Aerbajinai W, Lee K, Chin K, Rodgers GP. Glia maturation factor-γ negatively modulates TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages. J Immunol. 2013;190:6093–6103. doi: 10.4049/jimmunol.1203048. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bambouskova M, Gorvel L, Lampropoulou V, Sergushichev A, Loginicheva E, Johnson K, Korenfeld D, Mathyer ME, Kim H, Huang LH, et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ-ATF3 inflammatory axis. Nature. 2018;556:501–504. doi: 10.1038/s41586-018-0052-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernardes JP, Mishra N, Tran F, Bahmer T, Best L, Blase JI, Bordoni D, Franzenburg J, Geisen U, Josephs-Spaulding J, et al. Longitudinal multi-omics analyses identify responses of megakaryocytes, erythroid cells, and plasmablasts as hallmarks of severe COVID-19. Immunity. 2020;53:1296–1314. doi: 10.1016/j.immuni.2020.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–1045. doi: 10.1016/j.cell.2020.04.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bruchez A, Sha K, Johnson J, Chen L, Stefani C, McConnell H, Gaucherand L, Prins R, Matreyek KA, Hume AJ, et al. MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses. Science. 2020;370:241–247. doi: 10.1126/science.abb3753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Carroll B, Otten EG, Manni D, Stefanatos R, Menzies FM, Smith GR, Jurk D, Kenneth N, Wilkinson S, Passos JF, et al. Oxidation of SQSTM1/p62 mediates the link between redox state and protein homeostasis. Nat Commun. 2018;9:256. doi: 10.1038/s41467-017-02746-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chavan S, Mangalaparthi KK, Singh S, Renuse S, Vanderboom PM, Madugundu AK, Budhraja R, McAulay K, Grys TE, Rule AD, et al. Mass spectrometric analysis of urine from COVID-19 patients for detection of SARS-CoV-2 viral antigen and to study host response. J Proteome Res. 2021;20:3404–3413. doi: 10.1021/acs.jproteome.1c00391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–2629. doi: 10.1172/JCI137244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coughlin PB, Tetaz T, Salem HH. Identification and purification of a novel serine proteinase inhibitor. J Biol Chem. 1993;268:9541–9547. doi: 10.1016/S0021-9258(18)98385-7. [DOI] [PubMed] [Google Scholar]
  10. De Voeght, A., Calmes, D., Beck, F., Sylvestre, J.B., Delvenne, P., Peters, P., Vertenoeil, G., Baron, F., Layios, N., and Canivet, J.L. (2020). Thrombotic microvascular injury is not mediated by thrombotic microangiopathy despite systemic complement activation in COVID-19 patients. medRxiv, 2020.2006.2018.20115873.
  11. Deshpande C. Thromboembolic findings in COVID-19 autopsies: pulmonary thrombosis or embolism? Ann Intern Med. 2020;173:394–395. doi: 10.7326/M20-3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19) Front Immunol. 2020;11:827. doi: 10.3389/fimmu.2020.00827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt M S, Arts RJW, Oosting M, Moorlag SJCFM, Groh LA, Zwaag J, et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 2019;29:211–220. doi: 10.1016/j.cmet.2018.09.003. [DOI] [PubMed] [Google Scholar]
  14. Fabregat A, Sidiropoulos K, Viteri G, Marin-Garcia P, Ping P, Stein L, D’Eustachio P, Hermjakob H. Reactome diagram viewer: data structures and strategies to boost performance. Bioinformatics. 2017;34:1208–1214. doi: 10.1093/bioinformatics/btx752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fan Y, Zhang J, Cai L, Wang S, Liu C, Zhang Y, You L, Fu Y, Shi Z, Yin Z, et al. The effect of anti-inflammatory properties of ferritin light chain on lipopolysaccharide-induced inflammatory response in murine macrophages. Biochim Biophys Acta. 2014;1843:2775–2783. doi: 10.1016/j.bbamcr.2014.06.015. [DOI] [PubMed] [Google Scholar]
  16. Feng J, Ding C, Qiu N, Ni X, Zhan D, Liu W, Xia X, Li P, Lu B, Zhao Q, et al. Firmiana: towards a one-stop proteomic cloud platform for data processing and analysis. Nat Biotechnol. 2017;35:409–412. doi: 10.1038/nbt.3825. [DOI] [PubMed] [Google Scholar]
  17. Figarska SM, Vonk JM, Boezen HM. NFE2L2 polymorphisms, mortality, and metabolism in the general population. Physiol Genomics. 2014;46:411–417. doi: 10.1152/physiolgenomics.00178.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, Damoraki G, Gkavogianni T, Adami ME, Katsaounou P, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe. 2020;27:992–1000. doi: 10.1016/j.chom.2020.04.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith N, Péré H, Charbit B, Bondet V, Chenevier-Gobeaux C, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020;369:718–724. doi: 10.1126/science.abc6027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280. doi: 10.1016/j.cell.2020.02.052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hooftman A, Angiari S, Hester S, Corcoran SE, Runtsch MC, Ling C, Ruzek MC, Slivka PF, McGettrick AF, Banahan K, et al. The immunomodulatory metabolite itaconate modifies NLRP3 and inhibits inflammasome activation. Cell Metab. 2020;32:468–478. doi: 10.1016/j.cmet.2020.07.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021;19:141–154. doi: 10.1038/s41579-020-00459-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Jakoš T, Pišlar A, Jewett A, Kos J. Cysteine cathepsins in tumor-associated immune cells. Front Immunol. 2019;10:2037. doi: 10.3389/fimmu.2019.02037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jha AK, Huang SCC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42:419–430. doi: 10.1016/j.immuni.2015.02.005. [DOI] [PubMed] [Google Scholar]
  27. Jiang S, Zhang X, Yang Y, Hotez PJ, Du L. Neutralizing antibodies for the treatment of COVID-19. Nat Biomed Eng. 2020;4:1134–1139. doi: 10.1038/s41551-020-00660-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kvedaraite E, Hertwig L, Sinha I, Ponzetta A, Hed Myrberg I, Lourda M, Dzidic M, Akber M, Klingström J, Folkesson E, et al. Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity. Proc Natl Acad Sci USA. 2021;118:e2018587118. doi: 10.1073/pnas.2018587118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Leng W, Ni X, Sun C, Lu T, Malovannaya A, Jung SY, Huang Y, Qiu Y, Sun G, Holt MV, et al. Proof-of-concept workflow for establishing reference intervals of human urine proteome for monitoring physiological and pathological changes. Ebiomedicine. 2017;18:300–310. doi: 10.1016/j.ebiom.2017.03.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Li Q, Ai J, Song Z, Liu J, Shan B. 4–1BB (CD137) ligand enhanced anti-tumor immune response against mouse forestomach carcinoma in vivo. Cell Mol Immunol. 2008;5:379–384. doi: 10.1038/cmi.2008.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Li R, Zhang P, Wang Y, Tao K. Itaconate: a metabolite regulates inflammation response and oxidative stress. Oxid Med Cell Longev. 2020;2020:1–11. doi: 10.1155/2020/5404780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Li S, Paulsson KM, Chen S, Sjögren HO, Wang P. Tapasin is required for efficient peptide binding to transporter associated with antigen processing. J Biol Chem. 2000;275:1581–1586. doi: 10.1074/jbc.275.3.1581. [DOI] [PubMed] [Google Scholar]
  33. Lisi F, Zelikin AN, Chandrawati R. Nitric oxide to fight viral infections. Adv Sci. 2021;8:2003895. doi: 10.1002/advs.202003895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73:3221–3247. doi: 10.1007/s00018-016-2223-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lu L, Zhang H, Zhan M, Jiang J, Yin H, Dauphars DJ, Li SY, Li Y, He YW. Antibody response and therapy in COVID-19 patients: what can be learned for vaccine development. Sci China Life Sci. 2020;63:1833–1849. doi: 10.1007/s11427-020-1859-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Martin TR, Wurfel MM, Zanoni I, Ulevitch R. Targeting innate immunity by blocking CD14: novel approach to control inflammation and organ dysfunction in COVID-19 illness. Ebiomedicine. 2020;57:102836. doi: 10.1016/j.ebiom.2020.102836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N, Goldmann O, Binz T, Wegner A, Tallam A, Rausell A, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci USA. 2013;110:7820–7825. doi: 10.1073/pnas.1218599110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, Jedrychowski MP, Costa ASH, Higgins M, Hams E, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018;556:113–117. doi: 10.1038/nature25986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Mir N, D’Amico A, Dasher J, Tolwani A, Valentine V. Understanding the andromeda strain—the role of cytokine release, coagulopathy and antithrombin III in SARS-CoV2 critical illness. Blood Rev. 2021;45:100731. doi: 10.1016/j.blre.2020.100731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Moraes-Vieira PM, Yore MM, Sontheimer-Phelps A, Castoldi A, Norseen J, Aryal P, Simonyté Sjödin K, Kahn BB. Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4. Proc Natl Acad Sci USA. 2020;117:31309–31318. doi: 10.1073/pnas.2013877117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ni X, Sun C, Tian Y, Huang Y, Gong T, Song L, Yang X, Li K, Zheng N, Wang J, et al. Could urinary ACE2 protein level help identify individuals susceptible to SARS-CoV-2 infection and complication? Sci China Life Sci. 2020;63:1766–1767. doi: 10.1007/s11427-020-1759-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ong EZ, Chan YFZ, Leong WY, Lee NMY, Kalimuddin S, Haja Mohideen SM, Chan KS, Tan AT, Bertoletti A, Ooi EE, et al. A dynamic immune response shapes COVID-19 progression. Cell Host Microbe. 2020;27:879–882. doi: 10.1016/j.chom.2020.03.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pascarella G, Strumia A, Piliego C, Bruno F, Del Buono R, Costa F, Scarlata S, Agrò FE. COVID-19 diagnosis and management: a comprehensive review. J Intern Med. 2020;288:192–206. doi: 10.1111/joim.13091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rapkiewicz AV, Mai X, Carsons SE, Pittaluga S, Kleiner DE, Berger JS, Thomas S, Adler NM, Charytan DM, Gasmi B, et al. Megakaryocytes and platelet-fibrin thrombi characterize multiorgan thrombosis at autopsy in COVID-19: a case series. Eclinicalmedicine. 2020;24:100434. doi: 10.1016/j.eclinm.2020.100434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rau JC, Beaulieu LM, Huntington JA, Church FC. Serpins in thrombosis, hemostasis and fibrinolysis. J Thromb Haemost. 2007;5:102–115. doi: 10.1111/j.1538-7836.2007.02516.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Reid MA, Paik J, Locasale JW. A missing link to vitamin B12 metabolism. Cell. 2017;171:736–737. doi: 10.1016/j.cell.2017.10.030. [DOI] [PubMed] [Google Scholar]
  47. Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M. Global quantification of mammalian gene expression control. Nature. 2011;473:337–342. doi: 10.1038/nature10098. [DOI] [PubMed] [Google Scholar]
  48. Shen B, Yi X, Sun Y, Bi X, Du J, Zhang C, Quan S, Zhang F, Sun R, Qian L, et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell. 2020;182:59–72. doi: 10.1016/j.cell.2020.05.032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Shen H, Campanello GC, Flicker D, Grabarek Z, Hu J, Luo C, Banerjee R, Mootha VK. The human knockout gene CLYBL connects itaconate to vitamin B12. Cell. 2017;171:771–782. doi: 10.1016/j.cell.2017.09.051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Shi G, Kenney AD, Kudryashova E, Zani A, Zhang L, Lai KK, Hall-Stoodley L, Robinson RT, Kudryashov DS, Compton AA, et al. Opposing activities of IFITM proteins in SARS-CoV-2 infection. EMBO J. 2021;40:e106501. doi: 10.15252/embj.2020106501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Shu T, Ning W, Wu D, Xu J, Han Q, Huang M, Zou X, Yang Q, Yuan Y, Bie Y, et al. Plasma proteomics identify biomarkers and pathogenesis of COVID-19. Immunity. 2020;53:1108–1122. doi: 10.1016/j.immuni.2020.10.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Song JW, Lam SM, Fan X, Cao WJ, Wang SY, Tian H, Chua G H, Zhang C, Meng FP, Xu Z, et al. Omics-driven systems interrogation of metabolic dysregulation in COVID-19 pathogenesis. Cell Metab. 2020;32:188–202. doi: 10.1016/j.cmet.2020.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Strelko CL, Lu W, Dufort FJ, Seyfried TN, Chiles TC, Rabinowitz JD, Roberts MF. Itaconic acid is a mammalian metabolite induced during macrophage activation. J Am Chem Soc. 2011;133:16386–16389. doi: 10.1021/ja2070889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Strik MCM, Wolbink A, Wouters D, Bladergroen BA, Verlaan AR, van Houdt IS, Hijlkema S, Hack CE, Kummer JA. Intracellular serpin SERPINB6 (PI6) is abundantly expressed by human mast cells and forms complexes with β-tryptase monomers. Blood. 2004;103:2710–2717. doi: 10.1182/blood-2003-08-2981. [DOI] [PubMed] [Google Scholar]
  55. Tian W, Zhang N, Jin R, Feng Y, Wang S, Gao S, Gao R, Wu G, Tian D, Tan W, et al. Immune suppression in the early stage of COVID-19 disease. Nat Commun. 2020;11:5859. doi: 10.1038/s41467-020-19706-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M, et al. Presence of genetic variants among young men with severe COVID-19. JAMA. 2020;324:663–673. doi: 10.1001/jama.2020.13719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. van Hateren A, Elliott T. The role of MHC I protein dynamics in tapasin and TAPBPR-assisted immunopeptidome editing. Curr Opin Immunol. 2021;70:138–143. doi: 10.1016/j.coi.2021.06.016. [DOI] [PubMed] [Google Scholar]
  58. Wendt R, Thijs L, Kalbitz S, Mischak H, Siwy J, Raad J, Metzger J, Neuhaus B, Leyen H, Dudoignon E, et al. A urinary peptidomic profile predicts outcome in SARS-CoV-2-infected patients. Eclinicalmedicine. 2021;36:100883. doi: 10.1016/j.eclinm.2021.100883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny J M, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–362. doi: 10.1038/nature03711. [DOI] [PubMed] [Google Scholar]
  60. Yano M, Koumoto Y, Kanesaki Y, Wu X, Kido H. 20S proteasome prevents aggregation of heat-denatured proteins without PA700 regulatory subcomplex like a molecular chaperone. Biomacromolecules. 2004;5:1465–1469. doi: 10.1021/bm049957a. [DOI] [PubMed] [Google Scholar]
  61. Zhang C, Leng W, Sun C, Lu T, Chen Z, Men X, Wang Y, Wang G, Zhen B, Qin J. Urine proteome profiling predicts lung cancer from control cases and other tumors. Ebiomedicine. 2018;30:120–128. doi: 10.1016/j.ebiom.2018.03.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zhang F, Li X, Ni Y, Shan G, Gao Y. Preliminary study of the urinary proteome in Li and Han ethnic individuals from Hainan. Sci China Life Sci. 2020;63:125–137. doi: 10.1007/s11427-018-9485-4. [DOI] [PubMed] [Google Scholar]
  63. Zhang S, Jiao Y, Li C, Liang X, Jia H, Nie Z, Zhang Y. Dimethyl itaconate alleviates the inflammatory responses of macrophages in sepsis. Inflammation. 2021;44:549–557. doi: 10.1007/s10753-020-01352-4. [DOI] [PubMed] [Google Scholar]
  64. Zhang T, He Y, Xu W, Ma A, Yang Y, Xu KF. Clinical trials for the treatment of Coronavirus disease 2019 (COVID-19): a rapid response to urgent need. Sci China Life Sci. 2020;63:774–776. doi: 10.1007/s11427-020-1660-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zhang YL, Li Q, Yang XM, Fang F, Li J, Wang YH, Yang Q, Zhu L, Nie HZ, Zhang XL, et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-Rho GTPase-Hippo pathways. Cancer Res. 2018;78:2305–2317. doi: 10.1158/0008-5472.CAN-17-2867. [DOI] [PubMed] [Google Scholar]
  66. Zhao MM, Yang WL, Yang FY, Zhang L, Huang WJ, Hou W, Fan CF, Jin RH, Feng YM, Wang YC, et al. Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Sig Transduct Target Ther. 2021;6:134. doi: 10.1038/s41392-021-00558-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zheng HY, Zhang M, Yang CX, Zhang N, Wang XC, Yang XP, Dong XQ, Zheng YT. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell Mol Immunol. 2020;17:541–543. doi: 10.1038/s41423-020-0401-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhu L, Yang P, Zhao Y, Zhuang Z, Wang Z, Song R, Zhang J, Liu C, Gao Q, Xu Q, et al. Single-cell sequencing of peripheral mononuclear cells reveals distinct immune response landscapes of COVID-19 and influenza patients. Immunity. 2020;53:685–696. doi: 10.1016/j.immuni.2020.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Zhu, S., Liu, Y., Zhou, Z., Zhang, Z., Xiao, X., Liu, Z., Chen, A., Dong, X., Tian, F., Chen, S., et al. (2021). Genome-wide CRISPR activation screen identifies candidate receptors for SARS-CoV-2 entry. Sci China Life Sci doi: 10.1007/s11427-021-1990-5. [DOI] [PMC free article] [PubMed]

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