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

Abstract

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.

In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

“…Severely infected COVID-19 patient autopsy samples showed that microthrombi or immunothrombi is associated with a hyperinflammatory response [56,57]. Our findings are further supported by recent results in the human immune system humanized mouse model on histological changes in the lungs with SARS-CoV-2 infection [58,35,49].…”

“…Severely infected COVID-19 patient autopsy samples showed that microthrombi or immunothrombi is associated with a hyperinflammatory response[56,57]. Our findings are further supported by recent results in the human immune system humanized mouse model on histological changes in the lungs with SARS-CoV-2 infection[58,35,49].Our results suggest a critical role of integrins as an additional receptor to SARS-CoV-2 spike protein cell entry[59,60]. We observed induced expression of integrin α 5 and integrin α v in the lungs of SARS-CoV-2 infected K18-hACE2 mice whereas lung expression of hACE2 levels did not vary in SARS-CoV-2+Saline or ATN-161 treated mice, suggesting that SARS-…”

Inflammation control and improvement of cognitive function in COVID-19 infections: is there a role for kynurenine 3-monooxygenase inhibition?

“…Therefore, it will be important to examine levels of KP metabolites in the CNS of patients with COVID-19 (e.g., via CSF or postmortem brains) to confirm whether they correlate with peripheral levels. It would also be interesting to measure KP metabolite levels following administration of KMO inhibitors in a mouse model of COVID-19 [84] to examine whether KMO inhibition modulates levels of KP metabolites and reduces neuroinflammation in the CNS in vivo . Therefore, further studies are required to fully examine the role of KP in both the inflammatory response and cognitive dysfunction in patients with COVID-19.…”

SARS-CoV-2 in animals: From potential hosts to animal models

“…In addition, human ACE2 expressing mice provide a suitable tool to evaluate vaccines and therapeutics, as has been demonstrated by research groups worldwide (e.g., Hassan et al, 2020 ; Ku et al, 2020 ; Li et al, 2020a , Li et al, 2020b ; Seo and Jang, 2020 ; Sun et al, 2020a ; Zheng et al, 2020a ). A further approach to circumvent the lack of susceptibility of wild-type mice to SARS-CoV-2 is the use of mice displaying a humanized immune system induced by infusion of human hematopoietic stem cells, which leads to severe COVID-19-like symptoms in the respective mouse line ( Brumeanu et al, 2020 ). Besides the adaptations of mice to SARS-CoV-2, one could use a reverse approach and adapt the virus to mice ( Dinnon et al, 2020 ; Gu et al, 2020 ; Wang et al, 2020 ).…”