Animal models of mechanisms of <scp>SARS‐CoV‐2</scp> infection and <scp>COVID‐19</scp> pathology

Cleary, Simon J.; Pitchford, Simon; Amison, Richard T.; Carrington, Robert; Cabrera, Cecilia; Magnen, Mélia; Looney, Mark R.; Gray, Elaine; Page, Clive

doi:10.1111/bph.15143

Cited by 170 publications

(185 citation statements)

References 105 publications

(177 reference statements)

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“…There is a critical need for appropriate animal models to study SARS-CoV-2 infection and immunopathological responses 23 . The HIS-DRAGA mouse offers compelling advantages as a pre-clinical tool for SARS-COVID-19 research and for efficient and informative testing of vaccines and potential therapeutics.…”

Section: Discussionmentioning

confidence: 99%

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

Brumeanu

Vir

Shashikumar

et al. 2020

Preprint

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The current SARS-CoV-2 pandemic is accompanied by high morbidity and mortality rates, and there is a compelling need for effective vaccines and therapeutic agents to lessen the severity of COVID-19 disease. Appropriate animal models are essential for testing of vaccines and therapeutics and for mechanistic studies of infection and the host response. The Spike (S) protein of SARS-COV-2 has a high affinity for the human ACE2 receptor, which is expressed on multiple cell types including alveolar epithelial and vascular endothelial cells. Wild-type mice are not susceptible to developing coronavirus-mediated diseases. Accordingly, several human (h)ACE2 transgenic mouse models have been developed for coronavirus research. However, these mice have failed to closely mimic important aspects of the human immunopathological responses to SARS-CoV-2. We report herein that DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL-2R. gammac KO.NOD) mice infused with human hematopoietic stem cells from cord blood reconstitute a fully functional human immune system, as well as engraft human epithelial and endothelial cells, sustain SARS-CoV-2 infection, and develop severe COVID-19-like symptoms. In pilot experiments, infected mice developed parenchymal and epithelial lung infiltrations with granzyme B+ and perforin+ CD8+ T cells and alveolar CD61+ microthrombi, mimicking human immunopathological responses to SARS-CoV-2. We propose the DRAGA mouse as a novel pre-clinical tool for studying COVID-19 immunopathology and human immune responses to SARS-CoV-2, including events leading to the cytokine storm and coagulopathies, as well as for testing of candidate vaccines and therapeutics.

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Section: Discussionmentioning

confidence: 99%

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

Brumeanu

Vir

Shashikumar

et al. 2020

Preprint

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“…The results from that study show that both cats and ferrets were efficiently infected and could transmit the virus, dogs showed low susceptibility, while pigs and avian species were not permissive hosts. In addition, non-human primates (NHPs), hamsters and hACE2 transgenic or adenovirus transduced mice have also been evaluated as potential animal models for SARS-CoV-2 and seem to be susceptible showing mild to severe clinical signs (Cleary, Pitchford et al 2020;Lakdawala and Menachery 2020).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 infection, disease and transmission in domestic cats

Gaudreault

Trujillo

Carossino

et al. 2020

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease 2019 (COVID-19) and responsible for the current pandemic. Recent SARS-CoV-2 susceptibility and transmission studies in cats show that the virus can replicate in these companion animals and transmit to other cats. Here, we present an in-depth study of SARS-CoV-2 infection, associated disease and transmission dynamics in domestic cats. Six 4- to 5-month-old cats were challenged with SARS-CoV-2 via intranasal and oral routes simultaneously. One day post challenge (DPC), two sentinel contact cats were co-mingled with the principal infected animals. Animals were monitored for clinical signs, clinicopathological abnormalities and viral shedding throughout the 21 DPC observation period. Postmortem examinations were performed at 4, 7 and 21 DPC to investigate disease progression. Viral RNA was not detected in blood but transiently in nasal, oropharyngeal and rectal swabs and bronchoalveolar lavage fluid as well as various tissues. Tracheobronchoadenitis of submucosal glands with the presence of viral RNA and antigen was observed in airways of the infected cats on 4 and 7 DPC. Serology showed that both, principal and sentinel cats, developed SARS-CoV-2-specific and neutralizing antibodies to SARS-CoV-2 detectable at 7 DPC or 10 DPC, respectively. All animals were clinically asymptomatic during the course of the study and capable of transmitting SARS-CoV-2 to sentinels within 2 days of comingling. The results of this study are critical for our understanding of the clinical course of SARS-CoV-2 in a naturally susceptible host species, and for risk assessment of the maintenance of SARS-CoV-2 in felines and transmission to other animals and humans.

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“…Because no animal models are available that accurately re ect clinical symptoms (e.g. lung damage) of patients with severe COVID-19 [25][26][27][28][29] , ferrets, Syrian hamsters and rhesus monkeys have been used together for evaluation of SARS-COV-2 pathogenesis/transmission and to assess the e cacy of therapeutics and vaccines against COVID-19 [30][31][32][33] . In vivo challenge studies using these models has demonstrated that CT-P59 is capable of quickly decreasing virus titres, particularly improving clinical symptoms and pathological changes in ferrets.…”

Section: Discussionmentioning

confidence: 99%

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

Lee

Kim

Ryu

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 global pandemic. Vaccines and therapeutics are urgently needed for this highly transmissible virus. In this study, we screened human monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein from an antibody library constructed from peripheral blood mononuclear cells of a COVID-19 convalescent patient. A potent neutralizing antibody, termed CT-P59, was identified and found to be effective against various SARS-CoV-2 isolates including the D614G spike protein variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/SARS-CoV-2 RBD showed that CT-P59 blocks interaction regions of SARS-CoV-2 RBD for its cellular receptor, angiotensin converting enzyme 2 (ACE2). The binding orientation of CT-P59 is notably different from the previously reported neutralizing mAbs targeting SARS-CoV-2 RBD suggesting that CT-P59 can be a novel binder to SARS-CoV-2 RBD. Therapeutic effects of CT-P59 were evaluated in three animal models (ferret, hamster, and rhesus monkey), and a substantial reduction in viral titre along with alleviation of clinical symptoms was observed. These findings suggest that the human monoclonal antibody, CT-P59, is a promising therapeutic candidate for treatment of COVID-19.

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Animal models of mechanisms of SARS‐CoV‐2 infection and COVID‐19 pathology

Cited by 170 publications

References 105 publications

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

A Human-Immune-System (HIS) humanized mouse model (DRAGA: HLA-A2. HLA-DR4. Rag1 KO.IL-2Rγc KO. NOD) for COVID-19

SARS-CoV-2 infection, disease and transmission in domestic cats

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

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