Browse > Article
http://dx.doi.org/10.14348/molcells.2021.0094

Experimental Models for SARS-CoV-2 Infection  

Kim, Taewoo (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST))
Lee, Jeong Seok (GENOME INSIGHT Inc.)
Ju, Young Seok (Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST))
Abstract
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a novel virus that causes coronavirus disease 2019 (COVID-19). To understand the identity, functional characteristics and therapeutic targets of the virus and the diseases, appropriate infection models that recapitulate the in vivo pathophysiology of the viral infection are necessary. This article reviews the various infection models, including Vero cells, human cell lines, organoids, and animal models, and discusses their advantages and disadvantages. This knowledge will be helpful for establishing an efficient system for defense against emerging infectious diseases.
Keywords
coronavirus; COVID-19; infection model; organoid; SARS-CoV-2;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020). The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 583, 830-833.   DOI
2 Beigel, J.H., Tomashek, K.M., Dodd, L.E., Mehta, A.K., Zingman, B.S., Kalil, A.C., Hohmann, E., Chu, H.Y., Luetkemeyer, A., Kline, S., et al. (2020). Remdesivir for the treatment of Covid-19 - final report. N. Engl. J. Med. 383, 1813-1826.   DOI
3 Fujii, M., Matano, M., Toshimitsu, K., Takano, A., Mikami, Y., Nishikori, S., Sugimoto, S., and Sato, T. (2018). Human intestinal organoids maintain self-renewal capacity and cellular diversity in niche-inspired culture condition. Cell Stem Cell 23, 787-793.e6.   DOI
4 Hassan, A.O., Case, J.B., Winkler, E.S., Thackray, L.B., Kafai, N.M., Bailey, A.L., McCune, B.T., Fox, J.M., Chen, R.E., Alsoussi, W.B., et al. (2020). A SARS-CoV-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell 182, 744-753.e4.   DOI
5 Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., et al. (2020). SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271-280.e8.   DOI
6 Huang, J., Hume, A.J., Abo, K.M., Werder, R.B., Villacorta-Martin, C., Alysandratos, K.D., Beermann, M.L., Simone-Roach, C., Lindstrom-Vautrin, J., Olejnik, J., et al. (2020). SARS-CoV-2 infection of pluripotent stem cell-derived human lung alveolar type 2 cells elicits a rapid epithelial-intrinsic inflammatory response. Cell Stem Cell 27, 962-973.e7.   DOI
7 Korber, B., Fischer, W.M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E.E., Bhattacharya, T., Foley, B., et al. (2020). Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell 182, 812-827.e19.   DOI
8 Lancaster, M.A., Renner, M., Martin, C.A., Wenzel, D., Bicknell, L.S., Hurles, M.E., Homfray, T., Penninger, J.M., Jackson, A.P., and Knoblich, J.A. (2013). Cerebral organoids model human brain development and microcephaly. Nature 501, 373-379.   DOI
9 Montagnon, B.J., Vincent-Falquet, J.C., and Saluzzo, J.F. (1999). Experience with vero cells at Pasteur Merieux Connaught. Dev. Biol. Stand. 98, 137-140; discussion 167.
10 Maines, T.R., Chen, L.M., Matsuoka, Y., Chen, H., Rowe, T., Ortin, J., Falcon, A., Nguyen, T.H., Mai le, Q., Sedyaningsih, E.R., et al. (2006). Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. Proc. Natl. Acad. Sci. U. S. A. 103, 12121-12126.   DOI
11 Konowalchuk, J., Speirs, J.I., and Stavric, S. (1977). Vero response to a cytotoxin of Escherichia coli. Infect. Immun. 18, 775-779.   DOI
12 Cox, R.M., Wolf, J.D., and Plemper, R.K. (2021). Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat. Microbiol. 6, 11-18.   DOI
13 Sachs, N., Papaspyropoulos, A., Zomer-van Ommen, D.D., Heo, I., Bottinger, L., Klay, D., Weeber, F., Huelsz-Prince, G., Iakobachvili, N., Amatngalim, G.D., et al. (2019). Long-term expanding human airway organoids for disease modeling. EMBO J. 38, e100300.   DOI
14 van Riel, D., Munster, V.J., de Wit, E., Rimmelzwaan, G.F., Fouchier, R.A., Osterhaus, A.D., and Kuiken, T. (2007). Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am. J. Pathol. 171, 1215-1223.   DOI
15 Corbett, K.S., Flynn, B., Foulds, K.E., Francica, J.R., Boyoglu-Barnum, S., Werner, A.P., Flach, B., O'Connell, S., Bock, K.W., Minai, M., et al. (2020). Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544-1555.   DOI
16 Driouich, J.S., Cochin, M., Lingas, G., Moureau, G., Touret, F., Petit, P.R., Piorkowski, G., Barthelemy, K., Laprie, C., Coutard, B., et al. (2021). Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat. Commun. 12, 1735.   DOI
17 Winkler, E.S., Bailey, A.L., Kafai, N.M., Nair, S., McCune, B.T., Yu, J., Fox, J.M., Chen, R.E., Earnest, J.T., Keeler, S.P., et al. (2020). SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat. Immunol. 21, 1327-1335.   DOI
18 Munster, V.J., Feldmann, F., Williamson, B.N., van Doremalen, N., Perez-Perez, L., Schulz, J., Meade-White, K., Okumura, A., Callison, J., Brumbaugh, B., et al. (2020). Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature 585, 268-272.   DOI
19 Osada, N., Kohara, A., Yamaji, T., Hirayama, N., Kasai, F., Sekizuka, T., Kuroda, M., and Hanada, K. (2014). The genome landscape of the african green monkey kidney-derived vero cell line. DNA Res. 21, 673-683.   DOI
20 Richard, M., van den Brand, J.M.A., Bestebroer, T.M., Lexmond, P., de Meulder, D., Fouchier, R.A.M., Lowen, A.C., and Herfst, S. (2020). Influenza A viruses are transmitted via the air from the nasal respiratory epithelium of ferrets. Nat. Commun. 11, 766.   DOI
21 Wu, F., Zhao, S., Yu, B., Chen, Y.M., Wang, W., Song, Z.G., Hu, Y., Tao, Z.W., Tian, J.H., Pei, Y.Y., et al. (2020). A new coronavirus associated with human respiratory disease in China. Nature 579, 265-269.   DOI
22 Wyler, E., Mosbauer, K., Franke, V., Diag, A., Gottula, L.T., Arsie, R., Klironomos, F., Koppstein, D., Honzke, K., Ayoub, S., et al. (2021). Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy. iScience 24, 102151.   DOI
23 Yang, L., Han, Y., Nilsson-Payant, B.E., Gupta, V., Wang, P., Duan, X., Tang, X., Zhu, J., Zhao, Z., Jaffre, F., et al. (2020). A human pluripotent stem cellbased platform to study SARS-CoV-2 tropism and model virus infection in human cells and organoids. Cell Stem Cell 27, 125-136.e7.   DOI
24 Youk, J., Kim, T., Evans, K.V., Jeong, Y.I., Hur, Y., Hong, S.P., Kim, J.H., Yi, K., Kim, S.Y., Na, K.J., et al. (2020). Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. Cell Stem Cell 27, 905-919.e10.   DOI
25 Kapalczynska, M., Kolenda, T., Przybyla, W., Zajaczkowska, M., Teresiak, A., Filas, V., Ibbs, M., Blizniak, R., Luczewski, L., and Lamperska, K. (2018). 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch. Med. Sci. 14, 910-919.
26 Ettayebi, K., Crawford, S.E., Murakami, K., Broughman, J.R., Karandikar, U., Tenge, V.R., Neill, F.H., Blutt, S.E., Zeng, X.L., Qu, L., et al. (2016). Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387-1393.   DOI
27 Broutier, L., Andersson-Rolf, A., Hindley, C.J., Boj, S.F., Clevers, H., Koo, B.K., and Huch, M. (2016). Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat. Protoc. 11, 1724-1743.   DOI
28 Jary, A., Leducq, V., Malet, I., Marot, S., Klement-Frutos, E., Teyssou, E., Soulie, C., Abdi, B., Wirden, M., Pourcher, V., et al. (2020). Evolution of viral quasispecies during SARS-CoV-2 infection. Clin. Microbiol. Infect. 26, 1560.e1-1560.e4.
29 Woolsey, C., Borisevich, V., Prasad, A.N., Agans, K.N., Deer, D.J., Dobias, N.S., Heymann, J.C., Foster, S.L., Levine, C.B., Medina, L., et al. (2021). Establishment of an African green monkey model for COVID-19 and protection against re-infection. Nat. Immunol. 22, 86-98.   DOI
30 Yoon, K.J., Song, G., Qian, X., Pan, J., Xu, D., Rho, H.S., Kim, N.S., Habela, C., Zheng, L., Jacob, F., et al. (2017). Zika-virus-encoded NS2A disrupts mammalian cortical neurogenesis by degrading adherens junction proteins. Cell Stem Cell 21, 349-358.e6.   DOI
31 Han, Y., Duan, X., Yang, L., Nilsson-Payant, B.E., Wang, P., Duan, F., Tang, X., Yaron, T.M., Zhang, T., Uhl, S., et al. (2021). Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589, 270-275.   DOI
32 Ammerman, N.C., Beier-Sexton, M., and Azad, A.F. (2008). Growth and maintenance of Vero cell lines. Curr. Protoc. Microbiol. Appendix 4, Appendix 4E.
33 Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A.A., Kim, S., Wilson, C.J., Lehar, J., Kryukov, G.V., Sonkin, D., et al. (2012). The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607.   DOI
34 Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727-733.   DOI
35 Jacob, F., Pather, S.R., Huang, W.K., Zhang, F., Wong, S.Z.H., Zhou, H., Cubitt, B., Fan, W., Chen, C.Z., Xu, M., et al. (2020). Human pluripotent stem cell-derived neural cells and brain organoids reveal SARS-CoV-2 neurotropism predominates in choroid plexus epithelium. Cell Stem Cell 27, 937-950.e9.   DOI
36 Chu, H., Chan, J.F., Yuen, T.T., Shuai, H., Yuan, S., Wang, Y., Hu, B., Yip, C.C., Tsang, J.O., Huang, X., et al. (2020). Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study. Lancet Microbe 1, e14-e23.   DOI
37 Crignis, E.D., Romal, S., Carofiglio, F., Moulos, P., Verstegen, M.M.A., Khalid, M.M., Pourfarzad, F., Rao, S., Bazrafshan, A., Koutsothanassis, C., et al. (2020). Human liver organoids; a patient-derived primary model for HBV infection and related hepatocellular carcinoma. BioRxiv, https://doi.org/10.1101/568147
38 Enkirch, T. and von Messling, V. (2015). Ferret models of viral pathogenesis. Virology 479-480, 259-270.   DOI
39 Rogers, T.F., Zhao, F., Huang, D., Beutler, N., Burns, A., He, W.T., Limbo, O., Smith, C., Song, G., Woehl, J., et al. (2020). Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 369, 956-963.   DOI
40 Cugola, F.R., Fernandes, I.R., Russo, F.B., Freitas, B.C., Dias, J.L., Guimaraes, K.P., Benazzato, C., Almeida, N., Pignatari, G.C., Romero, S., et al. (2016). The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267-271.   DOI
41 Sato, T., Vries, R.G., Snippert, H.J., van de Wetering, M., Barker, N., Stange, D.E., van Es, J.H., Abo, A., Kujala, P., Peters, P.J., et al. (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262-265.   DOI
42 Zhou, J., Li, C., Sachs, N., Chiu, M.C., Wong, B.H., Chu, H., Poon, V.K., Wang, D., Zhao, X., Wen, L., et al. (2018). Differentiated human airway organoids to assess infectivity of emerging influenza virus. Proc. Natl. Acad. Sci. U. S. A. 115, 6822-6827.   DOI
43 Huch, M., Gehart, H., van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M.M., Ellis, E., van Wenum, M., Fuchs, S.A., de Ligt, J., et al. (2015). Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299-312.   DOI
44 Sia, S.F., Yan, L.M., Chin, A.W.H., Fung, K., Choy, K.T., Wong, A.Y.L., Kaewpreedee, P., Perera, R., Poon, L.L.M., Nicholls, J.M., et al. (2020). Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature 583, 834-838.   DOI
45 van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J.N., Port, J.R., Avanzato, V.A., Bushmaker, T., Flaxman, A., Ulaszewska, M., et al. (2020). ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 586, 578-582.   DOI
46 Wang, R., Simoneau, C.R., Kulsuptrakul, J., Bouhaddou, M., Travisano, K.A., Hayashi, J.M., Carlson-Stevermer, J., Zengel, J.R., Richards, C.M., Fozouni, P., et al. (2021). Genetic screens identify host factors for SARS-CoV-2 and common cold coronaviruses. Cell 184, 106-119.e14.   DOI
47 Zhang, Y., Zeng, G., Pan, H., Li, C., Hu, Y., Chu, K., Han, W., Chen, Z., Tang, R., Yin, W., et al. (2021). Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 21, 181-192.   DOI
48 Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., et al. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270-273.   DOI
49 Salawu, A., Fernando, M., Hughes, D., Reed, M.W., Woll, P., Greaves, C., Day, C., Alhajimohammed, M., and Sisley, K. (2016). Establishment and molecular characterisation of seven novel soft-tissue sarcoma cell lines. Br. J. Cancer 115, 1058-1068.   DOI
50 Sun, S.H., Chen, Q., Gu, H.J., Yang, G., Wang, Y.X., Huang, X.Y., Liu, S.S., Zhang, N.N., Li, X.F., Xiong, R., et al. (2020). A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe 28, 124-133.e4.   DOI
51 Pellegrini, L., Albecka, A., Mallery, D.L., Kellner, M.J., Paul, D., Carter, A.P., James, L.C., and Lancaster, M.A. (2020). SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell 27, 951-961.e5.   DOI
52 Walls, A.C., Park, Y.J., Tortorici, M.A., Wall, A., McGuire, A.T., and Veesler, D. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281-292.e6.   DOI
53 Xu, M., Lee, E.M., Wen, Z., Cheng, Y., Huang, W.K., Qian, X., Tcw, J., Kouznetsova, J., Ogden, S.C., Hammack, C., et al. (2016). Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101-1107.   DOI
54 Garcez, P.P., Loiola, E.C., Madeiro da Costa, R., Higa, L.M., Trindade, P., Delvecchio, R., Nascimento, J.M., Brindeiro, R., Tanuri, A., and Rehen, S.K. (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816-818.   DOI
55 Lee, J.S., Koh, J.Y., Yi, K., Kim, Y.I., Park, S.J., Kim, E.H., Kim, S.M., Park, S.H., Ju, Y.S., Choi, Y.K., et al. (2020). Single-cell transcriptome of bronchoalveolar lavage fluid reveals dynamic change of macrophages during SARS-CoV-2 infection in ferrets. BioRxiv, https://doi.org/10.1101/2020.11.18.388280
56 Monteil, V., Kwon, H., Prado, P., Hagelkruys, A., Wimmer, R.A., Stahl, M., Leopoldi, A., Garreta, E., Hurtado Del Pozo, C., Prosper, F., et al. (2020). Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 181, 905-913.e7.   DOI
57 Munoz-Fontela, C., Dowling, W.E., Funnell, S.G.P., Gsell, P.S., Riveros-Balta, A.X., Albrecht, R.A., Andersen, H., Baric, R.S., Carroll, M.W., Cavaleri, M., et al. (2020). Animal models for COVID-19. Nature 586, 509-515.   DOI
58 Kaptein, S.J.F., Jacobs, S., Langendries, L., Seldeslachts, L., Ter Horst, S., Liesenborghs, L., Hens, B., Vergote, V., Heylen, E., Barthelemy, K., et al. (2020). Favipiravir at high doses has potent antiviral activity in SARS-CoV2-infected hamsters, whereas hydroxychloroquine lacks activity. Proc. Natl. Acad. Sci. U. S. A. 117, 26955-26965.   DOI
59 Lamers, M.M., Beumer, J., van der Vaart, J., Knoops, K., Puschhof, J., Breugem, T.I., Ravelli, R.B.G., Paul van Schayck, J., Mykytyn, A.Z., Duimel, H.Q., et al. (2020). SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50-54.   DOI
60 Maher, J.A. and DeStefano, J. (2004). The ferret: an animal model to study influenza virus. Lab Anim. (N.Y.) 33, 50-53.   DOI
61 O'Driscoll, M., Ribeiro Dos Santos, G., Wang, L., Cummings, D.A.T., Azman, A.S., Paireau, J., Fontanet, A., Cauchemez, S., and Salje, H. (2021). Age-specific mortality and immunity patterns of SARS-CoV-2. Nature 590, 140-145.   DOI
62 Ramani, S., Crawford, S.E., Blutt, S.E., and Estes, M.K. (2018). Human organoid cultures: transformative new tools for human virus studies. Curr. Opin. Virol. 29, 79-86.   DOI
63 Kim, Y.I., Kim, S.G., Kim, S.M., Kim, E.H., Park, S.J., Yu, K.M., Chang, J.H., Kim, E.J., Lee, S., Casel, M.A.B., et al. (2020d). Infection and rapid transmission of SARS-CoV-2 in ferrets. Cell Host Microbe 27, 704-709.e2.   DOI
64 Jiang, R.D., Liu, M.Q., Chen, Y., Shan, C., Zhou, Y.W., Shen, X.R., Li, Q., Zhang, L., Zhu, Y., Si, H.R., et al. (2020). Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2. Cell 182, 50-58.e8.   DOI
65 Katsura, H., Sontake, V., Tata, A., Kobayashi, Y., Edwards, C.E., Heaton, B.E., Konkimalla, A., Asakura, T., Mikami, Y., Fritch, E.J., et al. (2020). Human lung stem cell-based alveolospheres provide insights into SARS-CoV-2-mediated interferon responses and pneumocyte dysfunction. Cell Stem Cell 27, 890-904.e8.   DOI
66 Kim, D., Lee, J.Y., Yang, J.S., Kim, J.W., Kim, V.N., and Chang, H. (2020a). The architecture of SARS-CoV-2 transcriptome. Cell 181, 914-921.e10.   DOI
67 Kim, J., Koo, B.K., and Knoblich, J.A. (2020b). Human organoids: model systems for human biology and medicine. Nat. Rev. Mol. Cell Biol. 21, 571-584.   DOI
68 Kim, J.M., Chung, Y.S., Jo, H.J., Lee, N.J., Kim, M.S., Woo, S.H., Park, S., Kim, J.W., Kim, H.M., and Han, M.G. (2020c). Identification of coronavirus isolated from a patient in Korea with COVID-19. Osong Public Health Res. Perspect. 11, 3-7.   DOI
69 Kim, Y.I., Kim, D., Yu, K.M., Seo, H.D., Lee, S.A., Casel, M.A.B., Jang, S.G., Kim, S., Jung, W., Lai, C.J., et al. (2021). Development of spike receptor-binding domain nanoparticles as a vaccine candidate against SARS-CoV-2 infection in ferrets. mBio 12, e00230-21.