Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection
Received date: 07 Oct 2020
Accepted date: 13 Nov 2020
Published date: 15 Sep 2021
Copyright
The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived selforganized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.
Key words: COVID-19; SARS-CoV-2; lung organoids; cell tropism; cellular metabolism; drug discovery
Rongjuan Pei , Jianqi Feng , Yecheng Zhang , Hao Sun , Lian Li , Xuejie Yang , Jiangping He , Shuqi Xiao , Jin Xiong , Ying Lin , Kun Wen , Hongwei Zhou , Jiekai Chen , Zhili Rong , Xinwen Chen . Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection[J]. Protein & Cell, 2021 , 12(9) : 717 -733 . DOI: 10.1007/s13238-020-00811-w
1 |
Anderson CM, Stahl A (2013) SLC27 fatty acid transport proteins. Mol Aspects Med 34:516–528
|
2 |
Banu N, Panikar SS, Leal LR, Leal AR (2020) Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to macrophage activation syndrome: therapeutic implications. Life Sci 256:117905
|
3 |
Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, Wei Q, Yu P, Xu Y, Qi F
|
4 |
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S
|
5 |
Bustamante-Marin XM, Ostrowski LE (2017) Cilia and mucociliary clearance. Cold Spring Harb Perspect Biol 9:a028241
|
6 |
Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11:85–95
|
7 |
Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224
|
8 |
Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M
|
9 |
Chandrashekar A, Liu J, Martinot AJ, McMahan K, Mercado NB, Peter L, Tostanoski LH, Yu J, Maliga Z, Nekorchuk M
|
10 |
Chen Y, Feng J, Zhao S, Han L, Yang H, Lin Y, Rong Z (2018) Longterm engraftment promotes differentiation of alveolar epithelial cells from human embryonic stem cell derived lung organoids. Stem Cells Dev 27:1339–1349
|
11 |
Clevers H (2016) Modeling development and disease with organoids. Cell 165:1586–1597
|
12 |
Daly JL, Simonetti B, Plagaro CA, Williamson MK, Shoemark DK, Simon-Gracia L, Klein K, Bauer M, Hollandi R, Greber UF
|
13 |
Damiani C, Rovida L, Maspero D, Sala I, Rosato L, Di Filippo M, Pescini D, Graudenzi A, Antoniotti M, Mauri G (2020) MaREA4-Galaxy: metabolic reaction enrichment analysis and visualization of RNA-seq data within Galaxy. Comput Struct Biotechnol J 18:993–999
|
14 |
Dawson PA, Hubbert ML, Rao A (2010) Getting the mOST from OST: role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism. Biochim Biophys Acta 1801:994–1004
|
15 |
Diamond DL, Syder AJ, Jacobs JM, Sorensen CM, Walters KA, Proll SC, McDermott JE, Gritsenko MA, Zhang Q, Zhao R
|
16 |
Dutta D, Clevers H (2017) Organoid culture systems to study hostpathogen interactions. Curr Opin Immunol 48:15–22
|
17 |
Eastman RT, Roth JS, Brimacombe KR, Simeonov A, Shen M, Patnaik S, Hall MD (2020) Remdesivir: a review of its discovery and development leading to emergency use authorization for treatment of COVID-19. ACS Cent Sci 6:672–683
|
18 |
Fehr AR, Perlman S (2015) Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282:1–23
|
19 |
Feingold KR, Grunfeld C (2000) Introduction to lipids and lipoproteins. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland HJ, Kaltsas G et al (eds) Endotext. MDText.com, South Dartmouth
|
20 |
Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7:489–503
|
21 |
Glowacka I, Bertram S, Herzog P, Pfefferle S, Steffen I, Muench MO, Simmons G, Hofmann H, Kuri T, Weber F
|
22 |
Harcourt J, Tamin A, Lu X, Kamili S, Sakthivel SK, Murray J, Queen K, Tao Y, Paden CR, Zhang J
|
23 |
Heaton NS, Randall G (2011) Multifaceted roles for lipids in viral infection. Trends Microbiol 19:368–375
|
24 |
Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S (2014) TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 88:1293–1307
|
25 |
Hilgenfeld R, Peiris M (2013) From SARS to MERS: 10 years of research on highly pathogenic human coronaviruses. Antiviral Res 100:286–295
|
26 |
Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A
|
27 |
Hollenbaugh JA, Munger J, Kim B (2011) Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology 415:153–159
|
28 |
Hotamisligil GS, Bernlohr DA (2015) Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol 11:592–605
|
29 |
Hou YXJ, Okuda K, Edwards CE, Martinez DR, Asakura T, DinnonKH T, Kato RE, Lee BL, Yount TM, Mascenik
|
30 |
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X
|
31 |
Hutchins AP, Jauch R, Dyla M, Miranda-Saavedra D (2014) glbase: a framework for combining, analyzing and displaying heterogeneous genomic and high-throughput sequencing data. Cell Regen (Lond) 3:1
|
32 |
Jiang RD, Liu MQ, Chen Y, Shan C, Zhou YW, Shen XR, Li Q, Zhang L, Zhu Y, Si HR
|
33 |
Jia MR, Wei T, Xu WF (2010) The analgesic activity of bestatin as a potent APN inhibitor. Front Neurosci 4:50
|
34 |
Kaye M (2006) SARS-associated coronavirus replication in cell lines. Emerg Infect Dis 12:128–133
|
35 |
Ketter E, Randall G (2019) Virus impact on lipids and membranes. Annu Rev Virol 6:319–340
|
36 |
Kim JM, Chung YS, Jo HJ, Lee NJ, Kim MS, Woo SH, Park S, Kim JW, Kim HM, Han MG (2020) Identification of Coronavirus Isolated from a Patient in Korea with COVID-19. Osong Public Health Res Perspect 11:3–7
|
37 |
Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482
|
38 |
Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W
|
39 |
Lamers MM, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem TI, Ravelli RBG, Paul van Schayck J, Mykytyn AZ, Duimel HQ
|
40 |
Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9:357–359
|
41 |
Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12:323–323
|
42 |
Li JY, You Z, Wang Q, Zhou ZJ, Qiu Y, Luo R, Ge XY (2020) The epidemic of 2019-novel-coronavirus (2019-nCoV) pneumonia and insights for emerging infectious diseases in the future. Microbes Infect 22:80–85
|
43 |
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550
|
44 |
Martic-Kehl MI, Schibli R, Schubiger PA (2012) Can animal data predict human outcome? Problems and pitfalls of translational animal research. Eur J Nucl Med Mol Imaging 39:1492–1496
|
45 |
McCauley KB, Hawkins F, Serra M, Thomas DC, Jacob A, Kotton DN (2017) Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of Wnt signaling. Cell Stem Cell 20(844–857):e846
|
46 |
Monteil V, Kwon H, Prado P, Hagelkruys A, Wimmer RA, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F
|
47 |
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J
|
48 |
Pan C, Kumar C, Bohl S, Klingmueller U, Mann M (2009) Comparative proteomic phenotyping of cell lines and primary cells to assess preservation of cell type-specific functions. Mol Cell Proteomics 8:443–450
|
49 |
Ramani S, Crawford SE, Blutt SE, Estes MK (2018) Human organoid cultures: transformative new tools for human virus studies. Curr Opin Virol 29:79–86
|
50 |
Risso D, Schwartz K, Sherlock G, Dudoit S (2011) GC-content normalization for RNA-Seq data.BMC Bioinformatics 12:480–480
|
51 |
Rockx B, Kuiken T, Herfst S, Bestebroer T, Lamers MM, Oude Munnink BB, de Meulder D, van Amerongen G, van den Brand J, Okba NMA
|
52 |
Rock JR, Randell SH, Hogan BL (2010) Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech 3:545–556
|
53 |
Rossi G, Manfrin A, Lutolf MP (2018) Progress and potential in organoid research. Nat Rev Genet 19:671–687
|
54 |
Ruprecht JJ, Kunji ERS (2020) The SLC25 mitochondrial carrier family: structure and mechanism. Trends Biochem Sci 45:244–258
|
55 |
Sanchez EL, Lagunoff M (2015) Viral activation of cellular metabolism. Virology 479–480:609–618
|
56 |
Schmitz G, Muller G (1991) Structure and function of lamellar bodies, lipid-protein complexes involved in storage and secretion of cellular lipids. J Lipid Res 32:1539–1570
|
57 |
Shi JZ, Wen ZY, Zhong GX, Yang HL, Wang C, Huang BY, Liu RQ, He XJ, Shuai L, Sun ZR
|
58 |
Shi R, Shan C, Duan X, Chen Z, Liu P, Song J, Song T, Bi X, Han C, Wu L
|
59 |
Sia SF, Yan LM, Chin AWH, Fung K, Choy KT, Wong AYL, Kaewpreedee P, Perera R, Poon LLM, Nicholls JM
|
60 |
Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, Zhu H, Zhao W, Han Y, Qin C (2019) From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 11:59
|
61 |
Song JW, Lam SM, Fan X, Cao WJ, Wang SY, Tian H, Chua GH, Zhang C, Meng FP, Xu Z
|
62 |
Sun D, Lennernas H, Welage LS, Barnett JL, Landowski CP, Foster D, Fleisher D, Lee KD, Amidon GL (2002) Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharm Res 19:1400–1416
|
63 |
Suzuki T, Ito Y, Sakai Y, Saito A, Okuzaki D, Motooka D, Minami S, Kobayashi T, Yamamoto T, Okamoto T
|
64 |
Takayama K (2020) In vitro and animal models for SARS-CoV-2 research. Trends Pharmacol Sci 41:513–517
|
65 |
Thaker SK, Ch’ng J, Christofk HR (2019) Viral hijacking of cellular metabolism. BMC Biol 17:59
|
66 |
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD (2020) Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med 382:1653–1659
|
67 |
van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato V, Bushmaker T, Flaxman A, Ulaszewska M
|
68 |
van Hemert MJ, van den Worm SH, Knoops K, Mommaas AM, Gorbalenya AE, Snijder EJ (2008) SARS-coronavirus replication/transcription complexes are membrane-protected and need a host factor for activity in vitro. PLoS Pathog 4:e1000054
|
69 |
Verdecchia P, Cavallini C, Spanevello A, Angeli F (2020) The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 76:14–20
|
70 |
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q
|
71 |
Wang H, Airola MV, Reue K (2017) How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1131–1145
|
72 |
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G (2020a) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30:269–271
|
73 |
Warren HS, Tompkins RG, Moldawer LL, Seok J, Xu W, Mindrinos MN, Maier RV, Xiao W, Davis RW (2015) Mice are not men. Proc Natl Acad Sci USA 112:E345
|
74 |
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC (2020) Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 324:782–793
|
75 |
Wilk AJ, Rustagi A, Zhao NQ, Roque J, Martínez-Colón GJ, McKechnie JL, Ivison GT, Ranganath T, Vergara R, Hollis T
|
76 |
Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, van Doremalen N, Leighton I, Yinda CK, Perez-Perez L
|
77 |
Xiao L, Sakagami H, Miwa N (2020) ACE2: the key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: demon or angel? Viruses 12:491
|
78 |
Yamamoto Y, Gotoh S, Korogi Y, Seki M, Konishi S, Ikeo S, Sone N, Nagasaki T, Matsumoto H, Muro S
|
79 |
Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X, Tang X, Zhu J, Zhao Z, Jaffre F
|
80 |
Yu G, Wang L-G, Han Y, He Q-Y (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. Omics 16:284–287
|
81 |
Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, Nkolola JP, Liu J, Li Z, Chandrashekar A
|
82 |
Zhao B, Ni C, Gao R, Wang Y, Yang L, Wei J, Lv T, Liang J, Zhang Q, Xu W
|
83 |
Zhou X, Jiang W, Liu Z, Liu S, Liang X (2017) Virus infection and death receptor-mediated apoptosis. Viruses 9:316
|
84 |
Zhou J, Li C, Liu X, Chiu MC, Zhao X, Wang D, Wei Y, Lee A, Zhang AJ, Chu H
|
85 |
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL
|
86 |
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R
|
/
〈 | 〉 |