1887

Abstract

SARS-CoV-2 is the causative agent of COVID-19 and human infections have resulted in a global health emergency. Small animal models that reproduce key elements of SARS-CoV-2 human infections are needed to rigorously screen candidate drugs to mitigate severe disease and prevent the spread of SARS-CoV-2. We and others have reported that transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the Keratin 18 (K18) promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge. Here we report that some infected mice that survive challenge have residual pulmonary damages and persistent brain infection on day 28 post-infection despite the presence of anti-SARS-COV-2 neutralizing antibodies. Because of the hypersensitivity of K18-hACE2 mice to SARS-CoV-2 and the propensity of virus to infect the brain, we sought to determine if anti-infective biologics could protect against disease in this model system. We demonstrate that anti-SARS-CoV-2 human convalescent plasma protects K18-hACE2 against severe disease. All control mice succumbed to disease by day 7; however, all treated mice survived infection without observable signs of disease. In marked contrast to control mice, viral antigen and lesions were reduced or absent from lungs and absent in brains of antibody-treated mice. Our findings support the use of K18-hACE2 mice for protective efficacy studies of anti-SARS-CoV-2 medical countermeasures (MCMs). They also support the use of this system to study SARS-CoV-2 persistence and host recovery.

Funding
This study was supported by the:
  • Defense Health Agency
    • Principle Award Recipient: JosephW Golden
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. The Microbiology Society waived the open access fees for this article.
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001599
2021-05-07
2022-01-24
Loading full text...

Full text loading...

/deliver/fulltext/jgv/102/5/jgv001599.html?itemId=/content/journal/jgv/10.1099/jgv.0.001599&mimeType=html&fmt=ahah

References

  1. Chen N, Zhou M, Dong X, Qu J, Gong F. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395:507–513 [View Article][PubMed]
    [Google Scholar]
  2. Zhou P, Yang XL, Wang XG, Hu B, Zhang L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270–273 [View Article][PubMed]
    [Google Scholar]
  3. Yang X, Yu Y, Xu J, Shu H, Xia J. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8:475–481 [View Article][PubMed]
    [Google Scholar]
  4. Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med 2020; 217: [View Article][PubMed]
    [Google Scholar]
  5. Salimi S, Hamlyn JM. COVID-19 and Crosstalk with the hallmarks of aging. J Gerontol A Biol Sci Med Sci 2020; 75:e34–e41 [View Article][PubMed]
    [Google Scholar]
  6. Tang D, Comish P, Kang R. The hallmarks of COVID-19 disease. PLoS Pathog 2020; 16:e1008536 [View Article][PubMed]
    [Google Scholar]
  7. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the Cytokine Storm in COVID-19. J Infect 2020; 80:607–613 [View Article][PubMed]
    [Google Scholar]
  8. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med 2020; 217: [View Article][PubMed]
    [Google Scholar]
  9. Tan YK, Goh C, Leow AST, Tambyah PA, Ang A. COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature. J Thromb Thrombolysis 2020; 50:587–595 [View Article][PubMed]
    [Google Scholar]
  10. Rodriguez-Sevilla JJ, Rodó-Pin A, Espallargas I, Villar-García J, Molina L et al. Pulmonary embolism in patients with covid-19 pneumonia: The utility of d-dimer. Arch Bronconeumol 2020; 56:758–759 [View Article][PubMed]
    [Google Scholar]
  11. Sakr Y, Giovini M, Leone M, Pizzilli G, Kortgen A. Pulmonary embolism in patients with coronavirus disease-2019 (COVID-19) pneumonia: a narrative review. Ann Intensive Care 2020; 10:124 [View Article][PubMed]
    [Google Scholar]
  12. DosSantos MF, Devalle S, Aran V, Capra D, Roque NR. Neuromechanisms of SARS-CoV-2: A Review. Front Neuroanat 2020; 14:37 [View Article]
    [Google Scholar]
  13. Hopkins C, Surda P, Whitehead E, Kumar BN. Early recovery following new onset anosmia during the COVID-19 pandemic - an observational cohort study. J Otolaryngol Head Neck Surg 2020; 49:26 [View Article][PubMed]
    [Google Scholar]
  14. Natoli S, Oliveira V, Calabresi P, Maia LF, Pisani A. Does SARS-Cov-2 invade the brain? Translational lessons from animal models. Eur J Neurol 2020; 27:1764–1773 [View Article][PubMed]
    [Google Scholar]
  15. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther 2020; 12:69 [View Article][PubMed]
    [Google Scholar]
  16. Kingstone T, Taylor AK, O’Donnell CA, Atherton H, Blane DN. Finding the “right” GP: a qualitative study of the experiences of people with long-COVID. BJGP Open 2020; 4: [View Article][PubMed]
    [Google Scholar]
  17. Fraser E. Long term respiratory complications of covid-19. BMJ 2020; 370:m3001 [View Article][PubMed]
    [Google Scholar]
  18. Coronavirus disease (COVID-19) pandemic; 2021 https://www.who.int/emergencies/diseases/novel-coronavirus-2019
  19. Shang J, Ye G, Shi K, Wan Y, Luo C. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020; 581:221–224 [View Article][PubMed]
    [Google Scholar]
  20. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181:e278 [View Article]
    [Google Scholar]
  21. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367:1260–1263 [View Article][PubMed]
    [Google Scholar]
  22. Lan J, Ge J, Yu J, Shan S, Zhou H. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020; 581:215–220 [View Article][PubMed]
    [Google Scholar]
  23. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 94:
    [Google Scholar]
  24. Lutz C, Maher L, Lee C, Kang W. COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice. Hum Genomics 2020; 14:20 [View Article][PubMed]
    [Google Scholar]
  25. Golden JW, Cline CR, Zeng X, Garrison AR, Carey BD. Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease. JCI Insight 2020; 5:19 [View Article]
    [Google Scholar]
  26. Bao L, Deng W, Huang B, Gao H, Liu J. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature 2020
    [Google Scholar]
  27. Zheng J, Roy Wong LY, Li K, Verma AK, Ortiz M et al. K18-hace2 mice for studies of covid-19 treatments and pathogenesis including anosmia. bioRxiv 2020 [View Article]
    [Google Scholar]
  28. Winkler ES, Bailey AL, Kafai NM, Nair S, McCune BT. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol 2020; 21:1327–1335 [View Article][PubMed]
    [Google Scholar]
  29. McCray PB, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol 2007; 81:813–821 [View Article][PubMed]
    [Google Scholar]
  30. Sun SH, Chen Q, HJ G, Yang G, Wang YX. A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe 2020
    [Google Scholar]
  31. Dinnon KH, Leist SR, Schafer A, Edwards CE, Martinez DR. A mouse-adapted SARS-CoV-2 model for the evaluation of COVID-19 medical countermeasures. bioRxiv 2020
    [Google Scholar]
  32. Hassan AO, Case JB, Winkler ES, Thackray LB, Kafai NM et al. A sars-cov-2 infection model in mice demonstrates protection by neutralizing antibodies. Cell 2020; 182:744–753 [View Article]
    [Google Scholar]
  33. Chan JF, Zhang AJ, Yuan S, Poon VK, Chan CC. Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: implications for disease pathogenesis and transmissibility. Clin Infect Dis 2020
    [Google Scholar]
  34. Brocato RL, Principe LM, Kim RK, Zeng X, Williams JA. Disruption of Adaptive Immunity Enhances Disease in SARS-CoV-2-Infected Syrian Hamsters. J Virol 2020; 94:22 [View Article]
    [Google Scholar]
  35. Lu S, Zhao Y, Yu W, Yang Y, Gao J. Comparison of nonhuman primates identified the suitable model for COVID-19. Signal Transduct Target Ther 2020; 5:157 [View Article][PubMed]
    [Google Scholar]
  36. Tseng CT, Huang C, Newman P, Wang N, Narayanan K. Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor. J Virol 2007; 81:1162–1173 [View Article][PubMed]
    [Google Scholar]
  37. Kwilas S, Kishimori JM, Josleyn M, Jerke K, Ballantyne J. A hantavirus pulmonary syndrome (HPS) DNA vaccine delivered using a spring-powered jet injector elicits a potent neutralizing antibody response in rabbits and nonhuman primates. Curr Gene Ther 2014; 14:200–210 [View Article][PubMed]
    [Google Scholar]
  38. Zhao YM, Shang YM, Song WB, QQ L, Xie H. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine 2020; 25:100463
    [Google Scholar]
  39. Huang Y, Tan C, Wu J, Chen M, Wang Z. Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respir Res 2020; 21:163 [View Article][PubMed]
    [Google Scholar]
  40. Klasse PJ, Moore JP. Antibodies to SARS-CoV-2 and their potential for therapeutic passive immunization. elife 2020; 9: [View Article]
    [Google Scholar]
  41. STH L, Lin HM, Baine I, Wajnberg A, Gumprecht JP. Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study. Nat Med 2020
    [Google Scholar]
  42. Imai M, Iwatsuki-Horimoto K, Hatta M, Loeber S, Halfmann PJ. Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc Natl Acad Sci U S A 2020; 117:16587–16595 [View Article][PubMed]
    [Google Scholar]
  43. Sia SF, Yan LM, Chin AWH, Fung K, Choy KT. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature 2020; 583:834–838 [View Article][PubMed]
    [Google Scholar]
  44. Chan CEZ, Seah SGK, Chye DH, Massey S, Torres M. The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody. bioRxiv 2020; 2020.2010.2026.355107:
    [Google Scholar]
  45. Hearn HJ, Soper WT, Miller WS. Loss in virulence of yellow fever virus serially passed in hela cells. Proc Soc Exp Biol Med 1965; 119:319–322 [View Article][PubMed]
    [Google Scholar]
  46. Golden JW, Beitzel B, Ladner JT, Mucker EM, Kwilas SA. An attenuated Machupo virus with a disrupted L-segment intergenic region protects guinea pigs against lethal Guanarito virus infection. Sci Rep 2017; 7:4679 [View Article][PubMed]
    [Google Scholar]
  47. Klimstra WB, Tilston-Lunel NL, Nambulli S, Boslett J, McMillen CM. SARS-CoV-2 growth, furin-cleavage-site adaptation and neutralization using serum from acutely infected hospitalized COVID-19 patients. J Gen Virol 2020; 101:1156–1169 [View Article][PubMed]
    [Google Scholar]
  48. Council NR Guide for the Care and Use of Laboratory Animals, 8th ed. Washington, D.C: National Academies Press; 2011
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001599
Loading
/content/journal/jgv/10.1099/jgv.0.001599
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error