Skip to main content
SpringerLink
Log in

Age associated susceptibility to SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model

  • ORIGINAL ARTICLE
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still an ongoing global health crisis. Clinical data indicate that the case fatality rate (CFR) is age dependent, with a higher CFR percentage in the elderly population. We compared the pathogenesis of SARS-CoV-2 in young and aged K18-hACE2 transgenic mice. We evaluated morbidity, mortality, viral titers, immune responses, and histopathology in SARS-CoV-2-infected young and old K18-hACE2 transgenic mice. Within the limitation of having a low number of mice per group, our results indicate that SARS-CoV-2 infection resulted in slightly higher morbidity, mortality, and viral replication in the lungs of old mice, which was associated with an impaired IgM response and altered cytokine and chemokine profiles. Results of this study increase our understanding of SARS-CoV-2 infectivity and immuno-pathogenesis in the elderly population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All authors agree that data will be available upon request.

References

  1. (WHO) WHO. WHO Coronavirus (COVID-19) Dashboard - https://covid19.who.int/ Geneva, Switzerland: WHO; 2023 .

  2. Remelli F, Volpato S, Trevisan C. Clinical features of SARS-CoV-2 infection in older adults. Clin Geriatr Med. 2022;38(3):483–500.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Oladunni FS, Park J-G, Pino PA, Gonzalez O, Akhter A, Allué-Guardia A, et al. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nat Commun. 2020;11(1):6122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Park JG, Pino PA, Akhter A, Alvarez X, Torrelles JB, Martinez-Sobrido L. Animal models of COVID-19: transgenic mouse model. Methods Mol Biol. 2022;2452:259–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Flurkey K, Currer JM, Harrison DE. Mouse models in aging research. In: Fox JG, Barthold SW, Davisson MT, Newcomer CE, Quimby FW, Smith AL, editors. The Mouse in Biomedical Research. 2nd Ed. New York; Elsevier. 2007;3:637–72.

  6. Farshbafnadi M, Kamali Zonouzi S, Sabahi M, Dolatshahi M, Aarabi MH. Aging & COVID-19 susceptibility, disease severity, and clinical outcomes: the role of entangled risk factors. Exp Gerontol. 2021;154:111507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liew FY, Girard JP, Turnquist HR. Interleukin-33 in health and disease. Nat Rev Immunol. 2016;16(11):676–89.

    Article  CAS  PubMed  Google Scholar 

  8. Gao Y, Cai L, Li L, Zhang Y, Li J, Luo C, et al. Emerging effects of IL-33 on COVID-19. Int J Mol Sci. 2022;23:21.

    Article  Google Scholar 

  9. Markovic SS, Jovanovic M, Gajovic N, Jurisevic M, Arsenijevic N, Jovanovic M, et al. IL 33 correlates with COVID-19 severity, radiographic and clinical finding. Front Med (Lausanne). 2021;8:749569.

    Article  PubMed  Google Scholar 

  10. Chen Y, Li C, Liu F, Ye Z, Song W, Lee ACY, et al. Age-associated SARS-CoV-2 breakthrough infection and changes in immune response in a mouse model. Emerg Microbes Infect. 2022;11(1):368–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang Y, Huang K, Wang T, Deng F, Gong W, Hui X, et al. SARS-CoV-2 rapidly adapts in aged BALB/c mice and induces typical pneumonia. J Virol. 2021;95:11.

    Article  Google Scholar 

  12. Davis MA, Voss K, Turnbull JB, Gustin AT, Knoll M, Muruato A, et al. A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery. Vaccines (Basel). 2022;11:1.

    Google Scholar 

  13. Assaid N, Arich S, Charoute H, Akarid K, Anouar Sadat M, Maaroufi A, et al. Kinetics of SARS-CoV-2 IgM and IgG antibodies 3 months after COVID-19 onset in Moroccan patients. Am J Trop Med Hyg. 2023;108(1):145–54.

    Article  CAS  PubMed  Google Scholar 

  14. Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med. 2020;26(6):845–8.

    Article  CAS  PubMed  Google Scholar 

  15. Zhou W, Xu X, Chang Z, Wang H, Zhong X, Tong X, et al. The dynamic changes of serum IgM and IgG against SARS-CoV-2 in patients with COVID-19. J Med Virol. 2021;93(2):924–33.

    Article  CAS  PubMed  Google Scholar 

  16. Barreiro P, Candel FJ, Sanz JC, San Roman J, Del Mar CM, Perez-Abeledo M, et al. Virological correlates of IgM-IgG patterns of response to SARS-CoV-2 infection according to targeted antigens. Viruses. 2021;13:5.

    Article  Google Scholar 

  17. Moreau GB, Burgess SL, Sturek JM, Donlan AN, Petri WA, Mann BJ. Evaluation of K18-hACE2 mice as a model of SARS-CoV-2 infection. Am J Trop Med Hyg. 2020;103(3):1215–9.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rathnasinghe R, Strohmeier S, Amanat F, Gillespie VL, Krammer F, Garcia-Sastre A, et al. Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection. Emerg Microbes Infect. 2020;9(1):2433–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Golden JW, Cline CR, Zeng X, Garrison AR, CareyBD, Mucker EM, et al. Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease. JCI Insight. 2020;5(19):e142032.

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Yinda CK, Port JR, Bushmaker T, Offei Owusu I, Purushotham JN, Avanzato VA, et al. K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathog. 2021;17(1):e1009195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Booeshaghi AP, L. Decrease in ACE2 mRNA expression in aged mouse lung. BioRxiv. 2020:1–2. [Pre-print]. https://www.biorxiv.org/content/https://doi.org/10.1101/2020.04.02.021451v1

  23. Viveiros A, Gheblawi M, Aujla PK, Sosnowski DK, Seubert JM, Kassiri Z, et al. Sex- and age-specific regulation of ACE2: insights into severe COVID-19 susceptibility. J Mol Cell Cardiol. 2022;164:13–6.

    Article  CAS  PubMed  Google Scholar 

  24. Moliva JI, Rajaram MV, Sidiki S, Sasindran SJ, Guirado E, Pan XJ, et al. Molecular composition of the alveolar lining fluid in the aging lung. Age (Dordr ). 2014;36(3):9633.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the Texas Biomedical Research Institute Biosafety Level 3 and Animal Biosafety Level 3 (BSL3/ABSL3) Operations Program for their assistance in maintaining exceptional facilities.

Funding

Studies were supported by a Texas Biomedical Research Institute (Texas Biomed) Forum Research grant awarded to J.T. and the National Institutes of Health/National Institute on Aging (NIH/NIA) 3P01-AG-051428-05S1 (Supplement) award to JT and JBT. Portions of this work benefited from the resources provided by the Interdisciplinary NextGen Tuberculosis Research Advancement Center (IN-TRAC) at Texas Biomed, which is supported by the NIAID/NIH under the award number P30AI168439. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Disease Intervention & Prevention Program, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    Varun Dwivedi, Jennifer Delgado, Amberlee Hicks, Marco Argonza, Reagan Meredith, Luis Martinez-Sobrido & Viraj Kulkarni

  2. Population Health Program, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    Vinay Shivanna, Shalini Gautam & Jordi B. Torrelles

  3. Host Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, 78227, USA

    Joanne Turner

  4. International Center for the Advancement of Research & Education (I•CARE), Texas Biomedical Research Institute, San Antonio, TX, USA

    Jordi B. Torrelles

Authors
  1. Varun Dwivedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vinay Shivanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shalini Gautam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jennifer Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amberlee Hicks
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marco Argonza
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reagan Meredith
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joanne Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Luis Martinez-Sobrido
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jordi B. Torrelles
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Viraj Kulkarni
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

V.D., V.S., V.K., S.G, J.D., A.H., and M.A., sample processing and data analysis; V.D., V.S., R.M., and V.K., analysis and data processing; L.M.S provided virus strain and developed protocols; V.D., V.K. J.B.T., and J.T., study conceptualization, experimental design, and wrote the manuscript preparation; J.T. provided funding. All authors read, edited, and approved the final version of this manuscript.

Corresponding authors

Correspondence to Joanne Turner, Luis Martinez-Sobrido, Jordi B. Torrelles or Viraj Kulkarni.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dwivedi, V., Shivanna, V., Gautam, S. et al. Age associated susceptibility to SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model. GeroScience 46, 2901–2913 (2024). https://doi.org/10.1007/s11357-024-01102-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-024-01102-6

Keywords

Search

Navigation