Recent Advances in Preclinical SARS-CoV-2 Research

There has been incredible scientific effort and progress over the past two years geared at the protection and treatment of COVID-19. On the preclinical side, developing translational COVID-19 models that closely mimic the clinical progression of the disease is vital to understand the disease and how we can treat patients effectively. The challenges in developing such models are numerous. They include infecting and replicating SARS-CoV-2 in host subjects, developing clinical characteristics of COVID-19, and ensuring that the research model is reproducible.

In this blog, we will highlight some significant recent advances in SARS-CoV-2 preclinical modelling, which use the inExpose to deliver inhaled target compounds and the flexiVent to characterize a full pulmonary function profile.

Preclinical efficacy and safety of novel SNAT against SARS–CoV–2 using a hamster model. (2022). Pokhrel, L.R., et al. Drug Delivery and Translational Research, 849

This group developed a novel antiviral nanodrug named Smart Nano-Enabled Antiviral Therapeutic (SNAT) with both an in vitro and in vivo approach
The inExpose aerosol inhalation system was used to effectively deliver SNAT to SARS-CoV-2 infected hamsters.
Results demonstrate that SNAT indeed had a therapeutic effect, whereas this compound reduced SARS-CoV-2 virus load, reversed body weight loss and improved overall lung health in infected hamsters.
Using human cells, SNAT was also shown to have antioxidant properties, specifically affecting lipid peroxidation

Syrian hamsters as a model of lung injury with SARS–CoV–2 infection: Pathologic, physiologic, and detailed molecular profiling. (2022) Bednash, J.S., et al. Translational Research 240, 1-16

Bednash and team investigated a SARS-CoV-2 infection model in hamsters and demonstrated key features of experimental acute respiratory distress syndrome (ARDS)
Using the flexiVent, pulmonary compliance, resistance and pressure-volume loops were measured in this SARS-CoV-2 hamster model.
Results demonstrated that hamsters exposed to SARS-CoV-2 exhibited acute inflammation, pulmonary permeability, hypoxemia and lung injury.

Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice. (2021). Case, J., et al. Cell Host Microbe, 29(7): 1151-1161

Michael Diamond’s group at the University of Washington investigated ultrapotent miniproteins (LCB1) as a novel means of targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).These specific miniproteins target the Receptor Binding Domain (RBD) on the spike protein of SARS-CoV-2.
In this study, the potential prophylactic and post-infection therapeutic effects of two LCB1 miniproteins were studied; with (LCB1-fc) and without (LCB1v1.3) an Fc domain. LCB1-fc contains a longer half-life and ability to engage the effector arms of the immune system.
Lung function results using the flexiVent system demonstrated a compromised lung function in SARS-CoV-2 infected mice without LCB1 treatment, such that a significant decrease in lung capacity and compliance as well as an increase in pulmonary resistance, elastance and tissue damping was seen. On the other hand, prophylactic LCB1-Fc treatment prevented this lung function decline in SARS-CoV-2 infected mice.

Additional recent COVID-19 Publications using SCIREQ Solutions:

Role of angiotensin-converting enzyme 2 in fine particulate matter-induced acute lung injury. (2022). Zhu, P. et al. Science of the Total Environment, 825, 153964

Alveolar regeneration following viral infection is independent of tuft cells. (2022). Huang, H., et al. bioRxiv, https://doi.org/10.1101/2022.03.11.483948

Eucalyptol inhaled during Invasive Mechanical Ventilation may attenuate Lung Injury caused by oxygen therapy in the management of COVID-19. (2022) Serra, D.S., et al. Australian Journal of Basic and Applied Sciences 16(4): 1-10

SARS–CoV–2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. (2020). Winkler, E.S. et al (2020). Nature Immunology volume 21, pages1327–1335

Loss of furin cleavage site attenuates SARS–CoV–2 pathogenesis. (2021). Johnson, B.A et al. Nature volume 591, pages293–299

SARS–CoV–2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function. (2020). Winkler, E.S., et al. BioRxiv, doi: https://doi.org/10.1101/2020.07.09.196188

E-cigarette-induced pulmonary inflammation and dysregulated repair are mediated by nAChR α7 receptor: role of nAChR α7 in SARS-CoV-2 Covid-19 ACE2 receptor regulation. (2020). Wang, Q., et al. Respiratory Research, 21: 154

Human neutralizing antibodies against SARS–CoV–2 require intact Fc effector functions for optimal therapeutic protection. (2021). Winkler, E., et al. Cell, 184(7): 1804-1820

Effect of Vaping on Lung Inflammation and SARS–CoV–2 Infection in a Hamster Model. (2022). Hinds, D., et al. ATS Journals

Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers. (2021). Nakayama, T., et al. Cell Reports Medicine, 2(10)

Cigarette Smoke Regulates Endothelial ACE2 Expression in the Lung. (2022). Xing, D.D. et al. ATS Journals

Pulmonary toxicity and inammatory response of ecigarettes containing medium-chain triglyceride oil

and vitamin E acetate: Implications in the pathogenesis of EVALI but independent of SARS-COV-2 COVID-19 related proteins. (2020). Muthumalage, T., et al. Research Square

Chronic E-Cigarette Aerosol Inhalation Alters the Immune State of the Lungs and Increases ACE2 Expression, Raising Concern for Altered Response and Susceptibility to SARS-CoV-2. (2021). Masso-Silva, J.A. Frontiers in Physiology, https://doi.org/10.3389/fphys.2021.649604

Sex differences in the induction of angiotensin converting enzyme 2 (ACE-2) in mouse lungs after e-cigarette vapor exposure and its relevance to COVID-19. (2021). Naidu, V., et al. Journal of Investigative Medicine, 69(5)

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19. (2021). Aloufi, N., et al. Lung Cellular and Molecular Physiology, 320(1): 152-157

Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19. (2020). Liu, Y., et al. Cell Research, 30: 1078-1087

Epithelial cell–specific loss of function of Miz1 causes a spontaneous COPD-like phenotype and up-regulates Ace2 expression in mice. (2020). Do-Umehara, H.C., et al. Science Advances, 6(33): DOI: 10.1126/sciadv.abb7238

Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19. (2020). Aloufi, N., et al. American Journal of Physiology Lung Cell Molecular Physiology, 320(1): 152-157

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