Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease

Long Fung   Chau; Simon Lillico; Tanja  Opriessnig; Rose Blake; Luc Tardy; Chen-Hsuin  Lee; Scott Maxwell; Claire Warren; Elisabeth Thornton; Catherine L McLaughlin; Gerry McLachlan; Christine Tait-Burkard; Sarah Fletcher; Stephen P Anderson; Sharon  Brown; Louise Gibbard; Thomas Tzelos; Dawn  MacMillan-Christensen; J Kenneth Baillie; Dorward David; David J Griffiths; Finn Grey

doi:10.1038/s41467-024-54615-1

Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease

Long Fung Chau, Simon Lillico, Tanja Opriessnig, Rose Blake, Luc Tardy, Chen-Hsuin Lee, Scott Maxwell, Claire Warren, Elisabeth Thornton, Catherine L McLaughlin, Gerry McLachlan, Christine Tait-Burkard, Sarah Fletcher, Stephen P Anderson, Sharon Brown, Louise Gibbard, Thomas Tzelos, Dawn MacMillan-Christensen, J Kenneth Baillie, Dorward DavidDavid J Griffiths^*, Finn Grey^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.

Original language	English
Article number	766
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	17 Jan 2025
DOIs	https://doi.org/10.1038/s41467-024-54615-1
Publication status	Published - 17 Jan 2025

Keywords / Materials (for Non-textual outputs)

Angiotensin-Converting Enzyme 2/genetics
Animals
Animals, Genetically Modified
COVID-19/virology
Disease Models, Animal
Humans
Lung/pathology
SARS-CoV-2/genetics
Swine
Virus Replication/genetics

Access to Document

10.1038/s41467-024-54615-1Licence: Other

499154_2_merged_1731526984Accepted author manuscript, 2.11 MBLicence: Creative Commons: Attribution (CC-BY)
s41467-024-54615-1 (1)Final published version, 4.07 MBLicence: Creative Commons: Attribution (CC-BY)

1 Active
2 Finished

Understanding the basis of host resistance
Wilson, A.
1/04/23 → 31/03/28
Project: Research
Human ACE2 transgenic pigs: A large animal model for Covid-19
Grey, F., Baillie, K., Burdon, T., Griffith, D., Lillico, S., Tait-Burkard, C. & Whitelaw, B.
BBSRC
15/02/21 → 14/08/22
Project: Research
ISSF3 funding: Generation of a constitutive Cas9 pig for gene-level pharmaceutical target validation.
Baillie, K., Clohisey Hendry, S. & Lillico, S.
1/07/18 → 30/06/20
Project: University Awarded Project Funding

Cite this

Chau, L. F., Lillico, S., Opriessnig, T., Blake, R., Tardy, L., Lee, C.-H., Maxwell, S., Warren, C., Thornton, E., McLaughlin, C. L., McLachlan, G., Tait-Burkard, C., Fletcher, S., Anderson, S. P., Brown, S., Gibbard, L., Tzelos, T., MacMillan-Christensen, D., Baillie, J. K., ... Grey, F. (2025). Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease. Nature Communications, 16(1), 1-13. Article 766. https://doi.org/10.1038/s41467-024-54615-1

@article{afa8aeae776d4db38e984422dbb20e9f,

title = "Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease",

abstract = "Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.",

keywords = "Angiotensin-Converting Enzyme 2/genetics, Animals, Animals, Genetically Modified, COVID-19/virology, Disease Models, Animal, Humans, Lung/pathology, SARS-CoV-2/genetics, Swine, Virus Replication/genetics",

author = "Chau, {Long Fung} and Simon Lillico and Tanja Opriessnig and Rose Blake and Luc Tardy and Chen-Hsuin Lee and Scott Maxwell and Claire Warren and Elisabeth Thornton and McLaughlin, {Catherine L} and Gerry McLachlan and Christine Tait-Burkard and Sarah Fletcher and Anderson, {Stephen P} and Sharon Brown and Louise Gibbard and Thomas Tzelos and Dawn MacMillan-Christensen and Baillie, {J Kenneth} and Dorward David and {J Griffiths}, David and Finn Grey",

year = "2025",

month = jan,

day = "17",

doi = "10.1038/s41467-024-54615-1",

language = "English",

volume = "16",

pages = "1--13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Chau, LF, Lillico, S, Opriessnig, T, Blake, R, Tardy, L, Lee, C-H, Maxwell, S, Warren, C , Thornton, E , McLaughlin, CL , McLachlan, G , Tait-Burkard, C , Fletcher, S, Anderson, SP, Brown, S, Gibbard, L, Tzelos, T, MacMillan-Christensen, D, Baillie, JK, David, D, J Griffiths, D & Grey, F 2025, 'Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease', Nature Communications, vol. 16, no. 1, 766, pp. 1-13. https://doi.org/10.1038/s41467-024-54615-1

TY - JOUR

T1 - Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease

AU - Chau, Long Fung

AU - Lillico, Simon

AU - Opriessnig, Tanja

AU - Blake, Rose

AU - Tardy, Luc

AU - Lee, Chen-Hsuin

AU - Maxwell, Scott

AU - Warren, Claire

AU - Thornton, Elisabeth

AU - McLaughlin, Catherine L

AU - McLachlan, Gerry

AU - Tait-Burkard, Christine

AU - Fletcher, Sarah

AU - Anderson, Stephen P

AU - Brown, Sharon

AU - Gibbard, Louise

AU - Tzelos, Thomas

AU - MacMillan-Christensen, Dawn

AU - Baillie, J Kenneth

AU - David, Dorward

AU - J Griffiths, David

AU - Grey, Finn

PY - 2025/1/17

Y1 - 2025/1/17

N2 - Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.

AB - Animal models that accurately reflect COVID-19 are vital for understanding mechanisms of disease and advancing development of improved vaccines and therapeutics. Pigs are increasingly recognized as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans, and they present a more ethically viable alternative to non-human primates. However, pigs are not susceptible to SARS-CoV-2 infection which limits their utility as a model. To address this, we have developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection. Following challenge, clinical signs consistent with COVID-19, including fever, coughing and respiratory distress were observed, with virus replication detected in the nasal turbinates, trachea and lungs up to the study endpoint, seven days post-infection. Notably, examination of tissues revealed immunopathology in the lungs consistent with histological changes observed in fatal human COVID-19 cases. This study establishes human ACE2 transgenic pigs as a large animal model that accurately reflects many aspects of COVID-19 disease.

KW - Angiotensin-Converting Enzyme 2/genetics

KW - Animals

KW - Animals, Genetically Modified

KW - COVID-19/virology

KW - Disease Models, Animal

KW - Humans

KW - Lung/pathology

KW - SARS-CoV-2/genetics

KW - Swine

KW - Virus Replication/genetics

U2 - 10.1038/s41467-024-54615-1

DO - 10.1038/s41467-024-54615-1

M3 - Article

C2 - 39824810

SN - 2041-1723

VL - 16

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 766

ER -

Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

Understanding the basis of host resistance

Human ACE2 transgenic pigs: A large animal model for Covid-19

ISSF3 funding: Generation of a constitutive Cas9 pig for gene-level pharmaceutical target validation.

Cite this