Abstract:Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has caused extensive mortality and morbidity and wreaked havoc on socioeconomic structures. The urgent need to better understand SARS-CoV-2 biology and enable continued development of effective countermeasures is aided by the production of laboratory tools that facilitate SARS-CoV-2 research. We previously created a directly accessible SARS-CoV-2 t… Show more
“…Although live ancestral SARS-CoV-2 was not detected at 6 dpi in the brain tissue, the lesions identified in the brain of ancestral strain-infected mice indicate that virus may be replicating at very low levels or being cleared earlier than the Delta strain. Previous studies have identified live virus in the brain of K18-hACE2 mice infected with the ancestral strain at similar disease time points as those analyzed here ( 43 ). Further assays to determine virus growth and histopathology of brain tissue at earlier and later time points would help clarify if virus replication correlates with brain pathology.…”
Section: Discussionsupporting
confidence: 66%
“…SARS-CoV-2-ancestral strain (GenBank accession no. NC_045512.2 , MN908947.3 ) was generated as previously described ( 43 , 68 ). Briefly, 10 μg of pCC1-4K-SARSCoV-2-Wuhan-Hu1 (GenBank accession no.…”
SARS-CoV-2 variants, with the threat of increased transmissibility, infectivity, and immune escape, continue to emerge as the COVID-19 pandemic progresses. Detailing the pathogenesis of disease caused by SARS-CoV-2 variants, such as Delta, is essential to better understand the clinical threat caused by emerging variants and associated disease.
“…Although live ancestral SARS-CoV-2 was not detected at 6 dpi in the brain tissue, the lesions identified in the brain of ancestral strain-infected mice indicate that virus may be replicating at very low levels or being cleared earlier than the Delta strain. Previous studies have identified live virus in the brain of K18-hACE2 mice infected with the ancestral strain at similar disease time points as those analyzed here ( 43 ). Further assays to determine virus growth and histopathology of brain tissue at earlier and later time points would help clarify if virus replication correlates with brain pathology.…”
Section: Discussionsupporting
confidence: 66%
“…SARS-CoV-2-ancestral strain (GenBank accession no. NC_045512.2 , MN908947.3 ) was generated as previously described ( 43 , 68 ). Briefly, 10 μg of pCC1-4K-SARSCoV-2-Wuhan-Hu1 (GenBank accession no.…”
SARS-CoV-2 variants, with the threat of increased transmissibility, infectivity, and immune escape, continue to emerge as the COVID-19 pandemic progresses. Detailing the pathogenesis of disease caused by SARS-CoV-2 variants, such as Delta, is essential to better understand the clinical threat caused by emerging variants and associated disease.
“…Mouse #F2 regained its original weight and mobility by 9 dpi, while mouse #F1 was still 10% below its original weight and no amelioration of the clinical condition at 14 dpi. The results showing early weight loss in DRAGA mice at 1 dpi are in agreement with studies in SARS-CoV-2 infected human ACE2 transgenic mice, which also showed 5–10% body weight loss at 1 dpi and attributed to severe dehydration 52 , 53 Figure 4. Dynamics of body weight changes following SARS-CoV-2 infection of HIS-DRAGA mice.…”
We report a Human Immune System (HIS)-humanized mouse model (“DRAGA”: HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103
+
) CD8
+
and CD4
+
T cells were sequestered in epithelial (CD326
+
) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate
in vivo
human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.
“…(2021) made use of the k18-hACE2 model to better understand the effect of SARS-CoV-2 infection on lung and GI microbiome diversity, an important factor in the immune system of infected hosts. Additionally, Liu et al. (2021) used this model when they reverse-engineered SARS-CoV-2 clones that could be used to further understand viral pathogenesis, as well as COVID-19 variants.…”
COVID-19 is the most consequential pandemic of the 21st century. Since the earliest stage of the 2019-2020 epidemic, animal models have been useful in understanding the etiopathogenesis of SARS-CoV-2 infection and rapid development of vaccines/drugs to prevent, treat or eradicate SARS-CoV-2 infection. Early SARS-CoV-1 research using immortalized in-vitro cell lines have aided in understanding different cells and receptors needed for SARS-CoV-2 infection and, due to their ability to be easily manipulated, continue to broaden our understanding of COVID-19 disease in in-vivo models. The scientific community determined animal models as the most useful models which could demonstrate viral infection, replication, transmission, and spectrum of illness as seen in human populations. Until now, there have not been well-described animal models of SARS-CoV-2 infection although transgenic mouse models (i.e. mice with humanized ACE2 receptors with humanized receptors) have been proposed. Additionally, there are only limited facilities (Biosafety level 3 laboratories) available to contribute research to aid in eventually exterminating SARS-CoV-2 infection around the world. This review summarizes the most successful animal models of SARS-CoV-2 infection including studies in Non-Human Primates (NHPs) which were found to be susceptible to infection and transmitted the virus similarly to humans (e.g., Rhesus macaques, Cynomolgus, and African Green Monkeys), and animal models that do not require Biosafety level 3 laboratories (e.g., Mouse Hepatitis Virus models of COVID-19, Ferret model, Syrian Hamster model). Balancing safety, mimicking human COVID-19 and robustness of the animal model, the Murine Hepatitis Virus-1 Murine model currently represents the most optimal model for SARS-CoV-2/COVID19 research. Exploring future animal models will aid researchers/scientists in discovering the mechanisms of SARS-CoV-2 infection and in identifying therapies to prevent or treat COVID-19.
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