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Updated: Sep 14, 2025
Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
The GPR4 antagonist NE-52-QQ57 increases survival, mitigates the hyperinflammatory response and reduces viral load in
Xin-Jun Wu1, Karen A Oppelt2, Ming Fan3
1Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Abstract:
COVID-19 (Coronavirus disease 19) is caused by infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the respiratory system and other organ systems. Tissue injuries resulting from viral infection and host hyperinflammatory responses may lead to moderate to severe pneumonia, systemic complications, and even death. While anti-inflammatory agents have been used to treat patients with severe COVID-19, their therapeutic effects are limited. GPR4 (G protein-coupled receptor 4) is a pro-inflammatory receptor expressed on vascular endothelial cells, regulating leukocyte infiltration and inflammatory responses. In this study, we evaluated the effects of a GPR4 antagonist, NE-52-QQ57, in the SARS-CoV-2-infected K18-hACE2 transgenic mouse model. Our results demonstrated that GPR4 antagonist treatment increased the survival rate in this severe COVID-19 mouse model. The inflammatory response, characterized by proinflammatory cytokines and chemokines, was reduced in the GPR4 antagonist group compared with the vehicle group. Additionally, both SARS-CoV-2 RNA copy numbers and infectious viral titers in the mouse lung were decreased in the GPR4 antagonist group. The percentage of SARS-CoV-2 antigen-positive mouse brains was also decreased in the GPR4 antagonist group compared to the vehicle group. Furthermore, the GPR4 antagonist inhibited SARS-CoV-2 propagation in Vero E6 and Caco-2 cells. Together, these results suggest that GPR4 antagonism may be explored as a novel approach for the treatment of COVID-19 and other similar viral diseases.
Insights
A GPR4 antagonist drug improved survival rates in a severe COVID-19 mouse model by reducing inflammation and viral load. This suggests GPR4 antagonism could be a new treatment for COVID-19 and similar viral diseases.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- COVID-19, caused by SARS-CoV-2, leads to severe pneumonia and systemic complications.
- Current anti-inflammatory treatments for severe COVID-19 have limited efficacy.
- GPR4 is a pro-inflammatory receptor involved in regulating inflammatory responses.
Purpose of the Study:
- To evaluate the therapeutic potential of a GPR4 antagonist (NE-52-QQ57) in a SARS-CoV-2 infection model.
- To assess the impact of GPR4 antagonism on survival, inflammation, and viral load in COVID-19.
Main Methods:
- Utilized K18-hACE2 transgenic mice infected with SARS-CoV-2.
- Administered GPR4 antagonist NE-52-QQ57 or vehicle control.
- Measured survival rates, inflammatory markers, viral RNA, and infectious viral titers in lungs and brains.
- Assessed viral propagation in cell culture models (Vero E6 and Caco-2 cells).
Main Results:
- GPR4 antagonist treatment significantly increased survival rates in the COVID-19 mouse model.
- Reduced levels of pro-inflammatory cytokines and chemokines were observed in the GPR4 antagonist group.
- Decreased SARS-CoV-2 RNA copy numbers and infectious viral titers in mouse lungs.
- Lowered percentage of SARS-CoV-2 antigen-positive mouse brains.
- GPR4 antagonist inhibited SARS-CoV-2 propagation in cell cultures.
Conclusions:
- GPR4 antagonism demonstrates therapeutic benefits in a severe COVID-19 mouse model.
- Targeting GPR4 may mitigate hyperinflammatory responses and reduce viral load.
- GPR4 antagonism presents a potential novel therapeutic strategy for COVID-19 and related viral infections.
