OpenLB
Open Library of Bioscience
Advanced Search
Nature metabolism
07, 2021;3 (7): 909-922.

A multi-omics investigation of the composition and function of extracellular vesicles along the temporal trajectory of COVID-19.

Sin Man Lam, Chao Zhang, Zehua Wang, Zhen Ni, Shaohua Zhang, Siyuan Yang, Xiahe Huang, Lesong Mo, Jie Li, Bernett Lee, Mei Mei, Lei Huang, Ming Shi, Zhe Xu, Fan-Ping Meng, Wen-Jing Cao, Ming-Ju Zhou, Lei Shi, Gek Huey Chua, Bowen Li, Jiabao Cao, Jun Wang, Shilai Bao, Yingchun Wang, Jin-Wen Song, Fujie Zhang, Fu-Sheng Wang, Guanghou Shui
Author Information
  1. Sin Man Lam: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. ORCID
  2. Chao Zhang: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China. ORCID
  3. Zehua Wang: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. ORCID
  4. Zhen Ni: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  5. Shaohua Zhang: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  6. Siyuan Yang: Laboratory of Infectious Diseases Center, Beijing Ditan Hospital Capital Medical University, Beijing, China. ORCID
  7. Xiahe Huang: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  8. Lesong Mo: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  9. Jie Li: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  10. Bernett Lee: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  11. Mei Mei: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  12. Lei Huang: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  13. Ming Shi: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  14. Zhe Xu: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  15. Fan-Ping Meng: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  16. Wen-Jing Cao: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  17. Ming-Ju Zhou: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  18. Lei Shi: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China.
  19. Gek Huey Chua: LipidALL Technologies Company Limited, Changzhou, China.
  20. Bowen Li: LipidALL Technologies Company Limited, Changzhou, China.
  21. Jiabao Cao: University of the Chinese Academy of Sciences, Beijing, China.
  22. Jun Wang: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  23. Shilai Bao: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  24. Yingchun Wang: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  25. Jin-Wen Song: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China. songjinwenchina@yeah.net. ORCID
  26. Fujie Zhang: The Clinical and Research Center for Infectious Diseases, Beijing Ditan Hospital Capital Medical University, Beijing, China. treatment@chinaaids.cn. ORCID
  27. Fu-Sheng Wang: Department of Infectious Diseases, Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, Beijing, China. fswang302@163.com. ORCID
  28. Guanghou Shui: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. ghshui@genetics.ac.cn. ORCID
PMID: 34158670 DOI: 10.1038/s42255-021-00425-4

Abstract

Exosomes represent a subtype of extracellular vesicle that is released through retrograde transport and fusion of multivesicular bodies with the plasma membrane. Although no perfect methodologies currently exist for the high-throughput, unbiased isolation of pure plasma exosomes, investigation of exosome-enriched plasma fractions of extracellular vesicles can confer a glimpse into the endocytic pathway on a systems level. Here we conduct high-coverage lipidomics with an emphasis on sterols and oxysterols, and proteomic analyses of exosome-enriched extracellular vesicles (EVs hereafter) from patients at different temporal stages of COVID-19, including the presymptomatic, hyperinflammatory, resolution and convalescent phases. Our study highlights dysregulated raft lipid metabolism that underlies changes in EV lipid membrane anisotropy that alter the exosomal localization of presenilin-1 (PS-1) in the hyperinflammatory phase. We also show in vitro that EVs from different temporal phases trigger distinct metabolic and transcriptional responses in recipient cells, including in alveolar epithelial cells, which denote the primary site of infection, and liver hepatocytes, which represent a distal secondary site. In comparison to the hyperinflammatory phase, EVs from the resolution phase induce opposing effects on eukaryotic translation and Notch signalling. Our results provide insights into cellular lipid metabolism and inter-tissue crosstalk at different stages of COVID-19 and are a resource to increase our understanding of metabolic dysregulation in COVID-19.

References

  1. Mathieu, M., Martin-Jaular, L., Lavieu, G. & Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 21, 9–17 (2019). [PMID: 30602770]
  2. Hendrix, A. The nature of blood(y) extracellular vesicles. Nat. Rev. Mol. Cell Biol. 22, 243 (2021). [PMID: 33568799]
  3. Cocozza, F., Grisard, E., Martin-Jaular, L., Mathieu, M. & Théry, C. SnapShot: extracellular vesicles. Cell 182, 262–262.e1 (2020). [PMID: 32649878]
  4. Ayres, J. S. A metabolic handbook for the COVID-19 pandemic. Nat. Metab. 2, 572–585 (2020). [PMID: 32694793]
  5. Harding, C., Heuser, J. & Stahl, P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 97, 329–339 (1983). [PMID: 6309857]
  6. Izquierdo-Useros, N. et al. HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse? PLoS Pathog. 6, e1000740 (2010). [PMID: 20360840]
  7. Cosset, F. L. & Dreux, M. HCV transmission by hepatic exosomes establishes a productive infection. J. Hepatol. 60, 674–675 (2014). [PMID: 24512825]
  8. Singh, P. P., LeMaire, C., Tan, J. C., Zeng, E. & Schorey, J. S. Exosomes released from M. tuberculosis infected cells can suppress IFN-γ mediated activation of naïve macrophages. PLoS ONE 6, e18564 (2011). [PMID: 21533172]
  9. Subra, C., Laulagnier, K., Perret, B. & Record, M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89, 205–212 (2007). [PMID: 17157973]
  10. Song, J. W. et al. Omics-driven systems interrogation of metabolic dysregulation in COVID-19 pathogenesis. Cell Metab. 32, 188–202.e185 (2020). [PMID: 32610096]
  11. Möbius, W. et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic 4, 222–231 (2003). [PMID: 12694561]
  12. Pfrieger, F. W. & Vitale, N. Cholesterol and the journey of extracellular vesicles. J. Lipid Res. 59, 2255–2261 (2018). [PMID: 29678958]
  13. Daniloski, Z. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell 184(92), 105.e16 (2021).
  14. Hoffmann, H.-H. et al. Functional interrogation of a SARS-CoV-2 host protein interactome identifies unique and shared coronavirus host factors. Cell Host Microbe 29, 267–280.e5 (2021). [PMID: 33357464]
  15. Beloribi, S. et al. Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells. PLoS ONE 7, e47480 (2012). [PMID: 23094054]
  16. Rizzo, P. et al. COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm? Basic Res. Cardiol. 115, 31 (2020). [PMID: 32274570]
  17. Aguayo-Ortiz, R., Straub, J. E. & Dominguez, L. Influence of membrane lipid composition on the structure and activity of γ-secretase. Phys. Chem. Chem. Phys. 20, 27294–27304 (2018). [PMID: 30357233]
  18. Holmes, O., Paturi, S., Ye, W., Wolfe, M. S. & Selkoe, D. J. Effects of membrane lipids on the activity and processivity of purified γ-secretase. Biochemistry 51, 3565–3575 (2012). [PMID: 22489600]
  19. Levi, M., Thachil, J., Iba, T. & Levy, J. H. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 7, e438–e440 (2020). [PMID: 32407672]
  20. Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). [PMID: 32171076]
  21. McGonagle, D., O’Donnell, J. S., Sharif, K., Emery, P. & Bridgewood, C. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2, e437–e445 (2020). [PMID: 32835247]
  22. Acharya, D., Liu, G. & Gack, M. U. Dysregulation of type I interferon responses in COVID-19. Nat. Rev. Immunol. 20, 397–398 (2020). [PMID: 32457522]
  23. Muller, L., Hong, C. S., Stolz, D. B., Watkins, S. C. & Whiteside, T. L. Isolation of biologically-active exosomes from human plasma. J. Immunol. Methods 411, 55–65 (2014). [PMID: 24952243]
  24. Voisin, M. et al. Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor. Proc. Natl Acad. Sci. USA 114, E9346–E9355 (2017). [PMID: 29078321]
  25. Marcello, A. et al. The cholesterol metabolite 27-hydroxycholesterol inhibits SARS-CoV-2 and is markedly decreased in COVID-19 patients. Redox Biol. 36, 101682 (2020). [PMID: 32810737]
  26. Puri, A. et al. The neutral glycosphingolipid globotriaosylceramide promotes fusion mediated by a CD4-dependent CXCR4-utilizing HIV type 1 envelope glycoprotein. Proc. Natl Acad. Sci. USA 95, 14435–14440 (1998). [PMID: 9826718]
  27. Lorizate, M. et al. Comparative lipidomics analysis of HIV-1 particles and their producer cell membrane in different cell lines. Cell. Microbiol. 15, 292–304 (2013). [PMID: 23279151]
  28. Honsho, M. & Fujiki, Y. Plasmalogen homeostasis - regulation of plasmalogen biosynthesis and its physiological consequence in mammals. FEBS Lett. 591, 2720–2729 (2017). [PMID: 28686302]
  29. Blomqvist, M. et al. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur. J. Immunol. 39, 1726–1735 (2009). [PMID: 19582739]
  30. Buschard, K. et al. Sulfatide controls insulin secretion by modulation of ATP-sensitive K-channel activity and Ca-dependent exocytosis in rat pancreatic β-cells. Diabetes 51, 2514–2521 (2002). [PMID: 12145165]
  31. Hollstein, T. et al. Autoantibody-negative insulin-dependent diabetes mellitus after SARS-CoV-2 infection: a case report. Nat. Metab. 2, 1021–1024 (2020). [PMID: 32879473]
  32. Müller, J. A. et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat. Metab. 3, 149–165 (2021). [PMID: 33536639]
  33. Kapustin, A. N. & Shanahan, C. M. Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation. J. Physiol. 594, 2905–2914 (2016). [PMID: 26864864]
  34. Lembo, D., Cagno, V., Civra, A. & Poli, G. Oxysterols: an emerging class of broad spectrum antiviral effectors. Mol. Asp. Med. 49, 23–30 (2016). [DOI: 10.1016/j.mam.2016.04.003]
  35. Segala, G. et al. Dendrogenin A drives LXR to trigger lethal autophagy in cancers. Nat. Commun. 8, 1903 (2017). [PMID: 29199269]
  36. Küçük, O. et al. Inhibition of NK cell-mediated cytotoxicity by oxysterols. Cell. Immunol. 139, 541–549 (1992). [PMID: 1733518]
  37. Küçük, O. et al. Inhibition of cytolytic T lymphocyte activity by oxysterols. Lipids 29, 657–660 (1994). [PMID: 7815901]
  38. Jung, J. I. et al. Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator. Mol. Neurodegener. 10, 29 (2015). [PMID: 26169917]
  39. Jung, J. I. et al. Steroids as γ-secretase modulators. FASEB J. 27, 3775–3785 (2013). [PMID: 23716494]
  40. Tilvis, R. S., Valvanne, J. N., Strandberg, T. E. & Miettinen, T. A. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. Ann. Med. 43, 292–301 (2011). [PMID: 21254906]
  41. Parvez, M. K. et al. Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: cell culture and molecular docking study. Saudi Pharm. J. 27, 389–400 (2019). [PMID: 30976183]
  42. Risitano, A. M. et al. Complement as a target in COVID-19? Nat. Rev. Immunol. 20, 343–344 (2020). [PMID: 32327719]
  43. Shen, B. et al. Proteomic and metabolomic characterization of COVID-19 patient sera. Cell 182, 59–72.e15 (2020). [PMID: 32492406]
  44. Stahel, P. F. & Barnum, S. R. Complement inhibition in coronavirus disease (COVID)-19: a neglected therapeutic option. Front. Immunol. 11, 1661 (2020). [PMID: 32733489]
  45. Thomson, T. M., Toscano-Guerra, E., Casis, E. & Paciucci, R. C1 esterase inhibitor and the contact system in COVID-19. Br. J. Haematol. 190, 520–524 (2020). [PMID: 32531085]
  46. Java, A. et al. The complement system in COVID-19: friend and foe? JCI Insight 5, e140711 (2020).
  47. Looze, C. et al. Proteomic profiling of human plasma exosomes identifies PPARγ as an exosome-associated protein. Biochem. Biophys. Res. Commun. 378, 433–438 (2009). [PMID: 19028452]
  48. Luan, J., Lu, Y., Gao, S. & Zhang, L. A potential inhibitory role for integrin in the receptor targeting of SARS-CoV-2. J. Infect. 81, 318–356 (2020). [PMID: 32283163]
  49. Sigrist, C. J., Bridge, A. & Le Mercier, P. A potential role for integrins in host cell entry by SARS-CoV-2. Antivir. Res. 177, 104759 (2020). [PMID: 32130973]
  50. La Porta, C. A. M. & Zapperi, S. Estimating the binding of SARS-CoV-2 peptides to HLA class I in human subpopulations using artificial neural networks. Cell Syst. 11, 412–417.e412 (2020). [PMID: 32916095]
  51. Choy, R. W., Cheng, Z. & Schekman, R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc. Natl Acad. Sci. USA 109, E2077–E2082 (2012). [PMID: 22711829]
  52. Runz, H. et al. Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J. Neurosci. 22, 1679–1689 (2002). [PMID: 11880497]
  53. Weaver, T. E. & Whitsett, J. A. Function and regulation of expression of pulmonary surfactant-associated proteins. Biochem. J. 273, 249–264 (1991). [PMID: 1991023]
  54. Zhang, C., Wu, Z., Li, J. W., Zhao, H. & Wang, G. Q. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents 55, 105954 (2020). [PMID: 32234467]
  55. Vince, J. E. et al. The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation. Cell Rep. 25, 2339–2353.e2334 (2018). [PMID: 30485804]
  56. Zhang, C., Shi, L. & Wang, F.-S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol. Hepatol. 5, 428–430 (2020). [PMID: 32145190]
  57. Ibrahim, I. H. & Ellakwa, D. E. SUMO pathway, blood coagulation and oxidative stress in SARS-CoV-2 infection. Biochem Biophys. Rep. 26, 100938 (2021). [PMID: 33558851]
  58. Eyries, M. et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 46, 65–69 (2014). [PMID: 24292273]
  59. Banerjee, A. K. et al. SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell 183, 1325–1339.e1321 (2020). [PMID: 33080218]
  60. Schubert, K. et al. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat. Struct. Mol. Biol. 27, 959–966 (2020). [PMID: 32908316]
  61. Luiken, S. et al. NOTCH target gene HES5 mediates oncogenic and tumor suppressive functions in hepatocarcinogenesis. Oncogene 39, 3128–3144 (2020). [PMID: 32055024]
  62. Zhu, C. et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 10, eaat0344 (2018).
  63. Pagliari, F. et al. ssRNA Virus and Host Lipid Rearrangements: Is There a Role for Lipid Droplets in SARS-CoV-2 Infection? Front. Mol. Biosci. 7, 578964 (2020).
  64. Raven, F. et al. Soluble gamma-secretase modulators attenuate Alzheimer’s β-amyloid pathology and induce conformational changes in presenilin 1. EBioMedicine 24, 93–101 (2017). [PMID: 28919280]
  65. Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021). [PMID: 33753937]
  66. Bourgade, K., Dupuis, G., Frost, E. H. & Fülöp, T. Anti-viral properties of amyloid-β peptides. J. Alzheimers Dis. 54, 859–878 (2016). [PMID: 27392871]
  67. Soscia, S. J. et al. The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS ONE 5, e9505 (2010). [PMID: 20209079]
  68. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008). [PMID: 18604209]
  69. Bertolani, C. et al. Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am. J. Pathol. 169, 2042–2053 (2006). [PMID: 17148667]
  70. Shen, C. et al. The relationship between hepatic resistin overexpression and inflammation in patients with nonalcoholic steatohepatitis. BMC Gastroenterol. 14, 39 (2014). [PMID: 24559185]
  71. He, X. et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat. Med. 26, 672–675 (2020). [PMID: 32296168]
  72. Zou, L. et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N. Engl. J. Med. 382, 1177–1179 (2020). [PMID: 32074444]
  73. Honda, A. et al. Highly sensitive quantification of key regulatory oxysterols in biological samples by LC-ESI-MS/MS. J. Lipid Res. 50, 350–357 (2009). [PMID: 18815436]
  74. Chen, L. et al. Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing. J. Lipid Res. 60, 1765–1775 (2019). [PMID: 31455613]
  75. Washburn, M. P., Wolters, D. & Yates, J. R.III Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat. Biotechnol. 19, 242–247 (2001). [PMID: 11231557]
  76. Cumba Garcia, L. M., Peterson, T. E., Cepeda, M. A., Johnson, A. J. & Parney, I. F. Isolation and analysis of plasma-derived exosomes in patients with glioma. Front. Oncol. 9, 651 (2019). [PMID: 31380286]
  77. Thery, C., Amigorena, S., Raposo, G. & Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 30, 3.22.1–3.22.29 (2006). [DOI: 10.1002/0471143030.cb0322s30]
  78. Laulagnier, K. et al. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem. J. 380, 161–171 (2004). [PMID: 14965343]
  79. Li, H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics 34, 3094–3100 (2018). [PMID: 29750242]

Grants

  1. 81721002/National Natural Science Foundation of China (National Science Foundation of China)
  2. 92057202/National Natural Science Foundation of China (National Science Foundation of China)

MeSH Term

Biological Transport
COVID-19
Cell Fractionation
Cell Membrane
Chemical Fractionation
Cluster Analysis
Computational Biology
Exosomes
Extracellular Vesicles
Host-Pathogen Interactions
Humans
Lipidomics
Metabolome
Metabolomics
Retrospective Studies
SARS-CoV-2
Letter Research Support, Non-U.S. Gov't

Word Cloud

Similar Articles

Cited By