Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 117 | 2022
Review
Animal models and SARS-CoV-2-induced pulmonary and neurological injuries
1Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Desenvolvimento Tecnológico em Virologia, Rio de Janeiro, RJ, Brasil
2Fundação Oswaldo Cruz-Fiocruz, Instituto de Tecnologia em Imunobiológicos, Laboratório de Experimentação Animal, Rio de Janeiro, RJ, Brasil
3Fundação Oswaldo Cruz-Fiocruz, Instituto de Tecnologia em Imunobiológicos, Vice-Diretoria de Desenvolvimento Tecnológico, Laboratório de Tecnologia Imunológica, Rio de Janeiro, RJ, Brasil
4Fundação Oswaldo Cruz-Fiocruz, Instituto de Tecnologia em Imunobiológicos, Laboratório de Neurovirulência, Rio de Janeiro, RJ, Brasil
DOI: 10.1590/0074-02760220239
ABSTRACT
Laboratory animals are essential mainly for experiments aiming to study pathogenesis and evaluate antivirals and vaccines against emerging human infectious diseases. Preclinical studies of coronavirus disease 19 (COVID-19) pathogenesis have used several animal species as models: transgenic human ACE2 mice (K18 mice), inbred BALB/c or C57BL/6N mice, ferrets, minks, domestic cats and dogs, hamsters, and macaques. However, the choice of an animal model relies on several limitations. Besides the host susceptibility, the researcher’s experience with animal model management and the correct interpretation of clinical and laboratory records are crucial to succeed in preclinical translational research. Here, we summarise pathological and clinical findings correlated with virological data and immunological changes observed from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experimental infections using different well-established SARS-CoV-2 animal model species. This essay aims to critically evaluate the current state of animal model translation to clinical data, as described in the human SARS-CoV-2 infection.
REFERENCES
01. Muñoz-Fontela C, Dowling WE, Funnell SGP, Gsell PS, Riveros- Balta AX, Albrecht RA, et al. Animal models for COVID-19. Nature. 2020; 586(7830): 509-15.
02. Wu Z, McGoogan JM. Characteristics of and important lessons from the Coronavirus disease 2019 (COVID-19) Outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13): 1239-42.
03. Connors JM, Levy JH. Thromboinflammation and the hypercoagulability of COVID-19. J Thromb Haemost. 2020; 18(7): 1559-61.
04. Drucker DJ. Diabetes, obesity, metabolism, and SARS-CoV-2 infection: the end of the beginning. Cell Metab. 2020; 33(3): 479-98.
05. Azevedo RB, Botelho BG, de Hollanda JVG, Ferreira LVL, de Andrade LZJ, Oei SSML, et al. Covid-19 and the cardiovascular system: a comprehensive review. J Hum Hypertens. 2020; 35(1): 4-11.
06. Bonaventura A, Vecchié A, Dagna L, Martinod K, Dixon DL, Van Tassell BW, et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat Rev Immunol. 2020; 21(5): 319-29.
07. Liu Y, Garron TM, Chang Q, Su Z, Zhou C, Qiu Y, et al. Celltype apoptosis in lung during SARS-CoV-2 infection. Pathogens. 2021; 10(5): 509.
08. Patrì A, Vargas M, Buonanno P, Annunziata MC, Russo D, Staibano S, et al. From SARS-CoV-2 hematogenous spreading to endothelial dysfunction: clinical-histopathological study of cutaneous signs of COVID-19. Diagn Pathol. 2021; 16(1): 16.
09. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA, Pão CRR, et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood. 2020; 136(11): 1330-41.
10. Loganathan S, Kuppusamy M, Wankhar W, Gurugubelli KR, Mahadevappa VH, Lepcha L, et al. Angiotensin-converting enzyme 2 (ACE2): COVID 19 gate way to multiple organ failure syndromes. Respir Physiol Neurobiol. 2021; 283: 103548.
11. Brasen CL, Christensen H, Olsen DA, Kahns S, Andersen RF, Madsen JB, et al. Daily monitoring of viral load measured as SARSCoV- 2 antigen and RNA in blood, IL-6, CRP and complement C3d predicts outcome in patients hospitalized with COVID-19. Clin Chem Lab Med. 2021; 59(12): 1988-97.
12. Elsoukkary SS, Mostyka M, Dillard A, Berman DR, Ma LX, Chadburn A, et al. Autopsy findings in 32 patients with COVID-19: a single-institution experience. Pathobiology. 2021; 88(1): 56-68.
13. Calabrese F, Pezzuto F, Fortarezza F, Hofman P, Kern I, Panizo A, et al. Pulmonary pathology and COVID-19: lessons from autopsy. The experience of European pulmonary pathologists. Virchows Arch Int J Pathol. 2020; 477(3): 359-72.
14. Yachou Y, El Idrissi A, Belapasov V, Ait Benali S. Neuroinvasion, neurotropic, and neuroinflammatory events of SARS-CoV-2: understanding the neurological manifestations in COVID-19 patients. Neurol Sci. 2020; 41(10): 2657-69.
15. Natoli S, Oliveira V, Calabresi P, Maia LF, Pisani A. Does SARSCov- 2 invade the brain? Translational lessons from animal models. Eur J Neurol. 2020; 27(9): 1764-73.
16. Burks SM, Rosas-Hernandez H, Alejandro Ramirez-Lee M, Cuevas E, Talpos JC. Can SARS-CoV-2 infect the central nervous system via the olfactory bulb or the blood-brain barrier? Brain Behav Immun. 2021; 95: 7-14.
17. Olivarria GM, Cheng Y, Furman S, Pachow C, Hohsfield LA, Smith-Geater C, et al. Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18- human ACE2 transgenic mice. J Virol. 2022; 96(4): e0196921.
18. Bao L, Deng W, Huang B, Gao H, Liu J, Ren L, et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020; 583(7818): 830-3.
19. Jiao L, Yang Y, Yu W, Zhao Y, Long H, Gao J, et al. The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys. Signal Transduct Target Ther. 2021; 6(1): 169.
20. Hobbs EC, Reid TJ. Animals and SARS-CoV-2: species susceptibility and viral transmission in experimental and natural conditions, and the potential implications for community transmission. Transbound Emerg Dis. 2021; 68(4): 1850-67.
21. Soni S, Jiang Y, Tesfaigzi Y, Hornick JL, Çataltepe S. Comparative analysis of ACE2 protein expression in rodent, non-human primate, and human respiratory tract at baseline and after injury: a conundrum for COVID-19 pathogenesis. PLoS One. 2021; 16(2): e0247510.
22. Salguero FJ, White AD, Slack GS, Fotheringham SA, Bewley KR, Gooch KE, et al. Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19. Nat Commun. 2021; 12(1): 1260.
23. Halfmann PJ, Iida S, Iwatsuki-Horimoto K, Maemura T, Kiso M, Scheaffer SM, et al. SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters. Nature. 2022; 603(7902): 687-92.
24. Zheng J, Wong LR, Li K, Verma AK, Ortiz ME, Wohlford-Lenane C, et al. COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice. Nature. 2021; 589(7843): 603-7.
25. Biancatelli RMLC, Solopov PA, Sharlow ER, Lazo JS, Marik PE, Catravas JD. The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in ?18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2021; 321(2): L477-84.
26. Yan F, Li E, Wang T, Li Y, Liu J, Wang W, et al. Characterization of two heterogeneous lethal mouse-adapted SARS-CoV-2 variants recapitulating representative aspects of human COVID-19. Front Immunol. 2022; 13: 821664.
27. Carossino M, Kenney D, O’Connell AK, Montanaro P, Tseng AE, Gertje HP, et al. Fatal neurodissemination and SARS-CoV-2 tropism in K18-hACE2 mice is only partially dependent on hACE2 expression. Viruses. 2022; 14(3): 535.
28. Belser JA, Eckert AM, Tumpey TM, Maines TR. Complexities in ferret Influenza virus pathogenesis and transmission models. Microbiol Mol Biol Rev. 2016; 80(3): 733-44.
29. Henderson FW, Hu SC, Collier AM. Pathogenesis of respiratory syncytial virus infection in ferret and fetal human tracheas in organ culture. Am Rev Respir Dis. 1978; 118(1): 29-37.
30. Capraro GA, Johnson JB, Kock ND, Parks GD. Virus growth and antibody responses following respiratory tract infection of ferrets and mice with WT and P/V mutants of the paramyxovirus Simian Virus 5. Virology. 2008; 376(2): 416-28.
31. Chu YK, Ali GD, Jia F, Li Q, Kelvin D, Couch RC, et al. The SARSCoV ferret model in an infection-challenge study. Virology. 2008; 374(1): 151-63.
32. Kim YI, Kim SG, Kim SM, Kim EH, Park SJ, Yu KM, et al. Infection and rapid transmission of SARS-CoV-2 in ferrets. Cell Host Microbe. 2020; 27(5): 704-9.e2.
33. Munnink BBO, Sikkema RS, Nieuwenhuijse DF, Molenaar RJ, Munger E, Molenkamp R, et al. Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science. 2021; 371(6525): 172-7.
34. Oreshkova N, Molenaar RJ, Vreman S, Harders F, Oude Munnink BB, Hakze-van der Honing RW, et al. SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020. Eurosurveillance. 2020; 25(23): 2001005.
35. Doma?ska-Blicharz K, Or?owska A, Smreczak M, Niemczuk K, Iwan E, Bomba A, et al. Mink SARS-CoV-2 infection in Poland. J Vet Res. 2021; 65(1): 1-5.
36. Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science. 2020; 368(6494): 1016-20.
37. Mallapaty S. Coronavirus can infect cats — dogs, not so much. Nature. 2020; Available from: https://www.nature.com/articles/ d41586-020-00984-8.
38. Stout AE, André NM, Jaimes JA, Millet JK, Whittaker GR. Coronaviruses in cats and other companion animals: Where does SARSCoV- 2/COVID-19 fit? Vet Microbiol. 2020; 247: 108777
39. Kumar A, Pandey SN, Pareek V, Narayan RK, Faiq MA, Kumari C. Predicting susceptibility for SARS-CoV-2 infection in domestic and wildlife animals using ACE2 protein sequence homology. Zoo Biol. 2021; 40(1): 79-85.
40. Patania OM, Chiba S, Halfmann PJ, Hatta M, Maemura T, Bernard KA, et al. Pulmonary lesions induced by SARS-CoV-2 infection in domestic cats. Vet Pathol. 2022; 59(4): 696-706.
41. Rendon-Marin S, Martinez-Gutierrez M, Whittaker GR, Jaimes JA, Ruiz-Saenz J. SARS CoV-2 spike protein in silico interaction with ACE2 receptors from wild and domestic species. Front Genet. 2021; 12: 571707.
42. Hossain MG, Javed A, Akter S, Saha S. SARS-CoV-2 host diversity: an update of natural infections and experimental evidence. J Microbiol Immunol Infect Wei Mian Yu Gan Ran Za Zhi. 2021; 54(2): 175-81.
43. Tewari D, Boger L, Brady S, Livengood J, Killian ML, Nair MS, et al. Transmission of SARS-CoV-2 from humans to a 16-year-old domestic cat with comorbidities in Pennsylvania, USA. Vet Med Sci. 2022; 8(2): 899-906.
44. McAloose D, Laverack M, Wang L, Killian ML, Caserta LC, Yuan F, et al. From People to panthera: natural SARS-CoV-2 infection in tigers and lions at the Bronx Zoo. mBio. 2020; 11(5): e02220-20.
45. Palmer MV, Martins M, Falkenberg S, Buckley A, Caserta LC, Mitchell PK, et al. Susceptibility of white-tailed deer (Odocoileus virginianus) to SARS-CoV-2. J Virol. 2021; 95(11): e00083-21.
46. Tomris I, Bouwman KM, Adolfs Y, Noack D, van der Woude R, Kerster G, et al. Distinct spatial arrangements of ACE2 and TMPRSS2 expression in Syrian hamster lung lobes dictates SARSCoV- 2 infection patterns. PLoS Pathog. 2022; 18(3): e1010340.
47. Ku MW, Bourgine M, Authié P, Lopez J, Nemirov K, Moncoq F, et al. Intranasal vaccination with a lentiviral vector protects against SARS-CoV-2 in preclinical animal models. Cell Host Microbe. 2021; 29(2): 236-49.e6.
48. Gilliland T, Liu Y, Li R, Dunn M, Cottle E, Terada Y, et al. Protection of human ACE2 transgenic Syrian hamsters from SARS CoV-2 variants by human polyclonal IgG from hyper-immunized transchromosomic bovines. bioRxiv. 2021 [Preprint]. doi: 10.1101/2021.07.26.453840.
49. Zhai C, Wang M, Chung HJ, Hassan M, Lee S, Kim HJ, et al. Roborovski hamster (Phodopus roborovskii) strain SH101 as a systemic infection model of SARS-CoV-2. Virulence. 2021; 12(1): 2430-42.
50. Bednash JS, Kagan VE, Englert JA, Farkas D, Tyurina YY, Tyurin VA, et al. Syrian hamsters as a model of lung injury with SARSCoV- 2 infection: pathologic, physiologic, and detailed molecular profiling. Transl Res J Lab Clin Med. 2022; 240: 1-16.
51. Ohno M, Sasaki M, Orba Y, Sekiya T, Masum MA, Ichii O, et al. Abnormal blood coagulation and kidney damage in aged hamsters infected with severe acute respiratory syndrome coronavirus 2. Viruses. 2021; 13(11): 2137.
52. Ziegler CGK, Miao VN, Owings AH, Navia AW, Tang Y, Bromley JD, et al. Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19. Cell. 2021; 184(18): 4713-33.e22.
53. Reyna RA, Kishimoto-Urata M, Urata S, Makishima T, Paessler S, Maruyama J. Recovery of anosmia in hamsters infected with SARS-CoV-2 is correlated with repair of the olfactory epithelium. Sci Rep. 2022; 12(1): 628.
54. Bauer L, Rissmann M, Benavides FFW, Leijten L, van Run P, Begeman L, et al. In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants. Acta Neuropathol Commun. 2022; 10(1): 124.
55. Käufer C, Schreiber CS, Hartke AS, Denden I, Stanelle-Bertram S, Beck S, et al. Microgliosis and neuronal proteinopathy in brain persist beyond viral clearance in SARS-CoV-2 hamster model. EBio- Medicine. 2022; 79: 103999.
56. Chen Y, Liu L, Wei Q, Zhu H, Jiang H, Tu X, et al. Rhesus angiotensin converting enzyme 2 supports entry of severe acute respiratory syndrome coronavirus in Chinese macaques. Virology. 2008; 381(1): 89-97.
57. Zhao X, Chen D, Szabla R, Zheng M, Li G, Du P, et al. Broad and differential animal angiotensin-converting enzyme 2 receptor usage by SARS-CoV-2. J Virol. 2020; 94(18): e00940-20.
58. Shan C, Yao YF, Yang XL, Zhou YW, Gao G, Peng Y, et al. Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques. Cell Res. 2020; 30(8): 670-7.
59. Yu P, Qi F, Xu Y, Li F, Liu P, Liu J, et al. Age-related rhesus macaque models of COVID-19. Anim Models Exp Med. 2020; 3(1): 93-7.
60. Chandrashekar A, Liu J, Martinot AJ, McMahan K, Mercado NB, Peter L, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020; 369(6505): 812-7.
61. Rockx B, Kuiken T, Herfst S, Bestebroer T, Lamers MM, Oude Munnink BB, et al. Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model. Science. 2020; 368(6494): 1012-5.
62. Clancy CS, Shaia C, Munster V, de Wit E, Hawman D, Okumura A, et al. Histologic pulmonary lesions of SARS-CoV-2 in 4 nonhuman primate species: an institutional comparative review. Vet Pathol. 2022; 59(4): 673-80.
63. de Abreu FVS, Macedo MV, da Silva AJJ, de Oliveira CH, de Ottone VO, de Almeida MAB, et al. No Evidence of SARS-CoV-2 infection in neotropical primates sampled during COVID-19 pandemic in Minas Gerais and Rio Grande do Sul, Brazil. EcoHealth. 2021; 18(4): 414-20.
Financial support: FAPERJ (E-26/210.189/2020, E-26/210.189/2020, E-26/242/2020, E-26/200.882/2021).
+ Corresponding author: marcelop@ioc.fiocruz.br 
https://orcid.org/0000-0003-3462-7277
Received 10 October 2022
Accepted 29 November 2022
HOW TO CITE
Pinto MA, da Silva AS, Rodrigues DDRF, Müller R, de Vasconcelos GALBM, Neves PCC, et al. Animal models and SARS-CoV-2-induced pulmonary and neurological injuries. Mem Inst Oswaldo Cruz. 2022; 117: e220239.
