Animal Models for COVID-19 Therapeutic Development: Where We Are and Where We Need to Go

Song, Zhao; Fan, Jianglin; Liu, Enqi

doi:10.3389/fmicb.2022.907406

Cited by 7 publications

(10 citation statements)

References 35 publications

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“…One contributing reason for the shortage of new, more specific, and effective drugs is the lack of an appropriate, widely accessible animal model of COVID-19 or CSS. Natural and genetically modified species used to model different aspects of COVID-19 include mice, ferrets, cats, dogs, pigs, and non-human primates [ 77 , 78 , 79 , 80 , 81 ]. The models described for CSS include the Staphylococcal superantigen mutant model in rabbits [ 82 ], the hemolytic transfusion model in mice [ 83 ], and the reactions of dogs to anti-CD28 mAb [ 84 ], primates to simian immunodeficiency virus [ 85 ], or pigs to a virulent African swine fever virus [ 86 ], yet another porcine model utilized LPS to induce CSS along with ARDS [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19

Kökény

Bakos

Barta

et al. 2023

IJMS

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Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3–4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions.

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Section: Discussionmentioning

confidence: 99%

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19

Kökény

Bakos

Barta

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Natural and genetically modified species used to model different aspects of COVID-19 include mice, ferrets, cats, dogs, pigs, and non-human primates. [77][78][79][80][81] The models described for CSS include the Staphylococcal superantigen mutant model in rabbits, 82 the hemolytic transfusion model in mice, 83 and the reactions of dogs to anti-CD28 mAb, 84 or primates to simian immunodeficiency virus, 85 or pigs to a virulent African swine fever virus. 86 .…”

Section: Discussionmentioning

confidence: 99%

Zymosan-induced leukocyte and cytokine changes in pigs: a new model for streamlined drug testing against severe COVID-19

Kökény

Bakos

Barta

et al. 2022

Preprint

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Injection of 0.1 mg/kg zymosan in pigs i.v. elicited transient hemodynamic disturbance within minutes, without major blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This change was followed by a transient granulopenia with a trough at 1 h, and then, up to about 6 h, a major granulocytosis, resulting in a 3-4-fold increase of neutrophil-to-lymphocyte ratio (NLR). In parallel with the changes in WBC differential, qRT-PCR and ELISA analyses showed increased transcription and/or release of inflammatory cytokines and chemokines into blood, including IL-6, TNF-α, CCL-2, CXCL-10, and IL-1RA. The expression of IL-6 peaked at already 1.5-2.5 h, and we observed significant correlation between lymphopenia and IL-6 gene expression. While these changes are consistent with zymosan's known stimulatory effect on both the humoral and cellular arms of the innate immune system, what gives novel clinical relevance to the co-manifestation of above hemodynamic, hematological, and immune changes is that they represent independent bad prognostic indicators in terminal COVID-19 and other diseases involving cytokine storm. Thus, within a 6 h experiment, the model enables consecutive reproduction of a symptom triad that is characteristic of late-stage COVID-19. Given the limitations of modeling cytokine storm in animals and effectively treating severe COVID-19, the presented relatively simple large animal model may advance the R&D of drugs against these conditions. One of these disease markers (NLR), obtained from a routine laboratory endpoint (WBC differential), may also enable streamlining the model for high throughput drug screening.

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“…To introduce hACE-2 in mice, CRISPR/Cas9 knock-in technology or recombinant plasmids are used to construct permanent genetic alterations. The human lung ciliated epithelial cell-specific HFH4/FOXJ1 promoter, the human epithelial cell cytokeratin-18 (K18) promoter, and the mouse ACE2 (mACE2) promoter all regulate the production of hACE-2 (Zhao et al 2020a , b ). By employing reverse genetics or serial passaging, viruses can be modified to directly infect wide-type mice.…”

Section: Mouse Modelsmentioning

confidence: 99%

“…Compared to the existing animal models, the tree shrew is a little less vulnerable to SARS-CoV-2 infection and might not be an appropriate animal for COVID-19-related research. However, as an asymptomatic carrier, the tree shrew may serve as a significant intermediate host for the SARS-CoV-2 virus (Zhao et al 2020a , b ).…”

Section: Tree Shrew Modelsmentioning

confidence: 99%

Susceptibility of SARS Coronavirus-2 infection in domestic and wild animals: a systematic review

et al. 2022

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Animals and viruses have constantly been co-evolving under natural circumstances and pandemic like situations. They harbour harmful viruses which can spread easily. In the recent times we have seen pandemic like situations being created as a result of the spread of deadly and fatal viruses. Coronaviruses (CoVs) are one of the wellrecognized groups of viruses. There are four known genera of Coronavirus family namely, alpha (α), beta (β), gamma (γ), and delta (δ). Animals have been infected with CoVs belonging to all four genera. In the last few decades the world has witnessed an emergence of severe acute respiratory syndromes which had created a pandemic like situation such as SARS CoV, MERS-CoV. We are currently in another pandemic like situation created due to the uncontrolled spread of a similar coronavirus namely SARSCoV-2. These findings are based on a small number of animals and do not indicate whether animals can transmit disease to humans. Several mammals, including cats, dogs, bank voles, ferrets, fruit bats, hamsters, mink, pigs, rabbits, racoon dogs, and white-tailed deer, have been found to be infected naturally by the virus. Certain laboratory discoveries revealed that animals such as cats, ferrets, fruit bats, hamsters, racoon dogs, and white-tailed deer can spread the illness to other animals of the same species. This review article gives insights on the current knowledge about SARS-CoV-2 infection and development in animals on the farm and in domestic community and their impact on society.

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Animal Models for COVID-19 Therapeutic Development: Where We Are and Where We Need to Go

Cited by 7 publications

References 35 publications

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19

Zymosan Particle-Induced Hemodynamic, Cytokine and Blood Cell Changes in Pigs: An Innate Immune Stimulation Model with Relevance to Cytokine Storm Syndrome and Severe COVID-19

Zymosan-induced leukocyte and cytokine changes in pigs: a new model for streamlined drug testing against severe COVID-19

Susceptibility of SARS Coronavirus-2 infection in domestic and wild animals: a systematic review

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