GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice.

Jide Tian,Blake Middleton,Daniel L Kaufman

doi:10.3390/v13060966

Abstract

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.

Highlights

While GABA-Rs are well known for their role in neurotransmission in the central nervous system, these receptors are found on some cell types in the periphery, including cells of the immune system and lung epithelial cells
We found that GABA treatment reduced the pneumonitis, disease severity and death rate when given before or after the onset of symptoms, and that these effects were mediated through activating GABAA -Rs
GABAA-R agonists inhibit activated Th17 and Th1 responses and promote CD4+ and CD8+ Tregs [10,11,13]; since adaptive immune responses take about a week to arise, these abilities are unlikely to have contributed to GABA’s ability to attenuate disease very soon after mouse hepatitis virus (MHV)-1 infection. These effects on adaptive immune responses may be relevant for treating COVID-19 which has a longer disease course and in which high levels of circulating Th1, Th17, and Th2-secreted proteins are associated with severe illness [19,20]; (2) GABA treatment may have limited deleterious inflammatory responses to the infection by reducing viral loads in the lungs; (3) GABA and GABAA -R positive allosteric modulators (PAMs) reduce inflammation and improve alveolar fluid clearance and lung functional recovery in animal models of acute lung injury [23,24,25,27,28,29,30] and in ventilated patients [31,32,33], and could have exerted similar actions in the MHV-1-infected mice; (4)

Summary

Introduction

While GABA-Rs are well known for their role in neurotransmission in the central nervous system, these receptors are found on some cell types in the periphery, including cells of the immune system and lung epithelial cells. Lung epithelial cells express GABA-Rs. GABA, a GABAB -agonist (baclofen), and GABAA -R-positive allosteric modulators (PAMs) have been shown to reduce inflammation and improve alveolar fluid clearance and lung functional recovery in different rodent models of acute lung injury (e.g., endotoxin or ventilator-induced injuries [23,24,25,26,27,28,29,30]), as well as limit pulmonary inflammatory responses and improve clinical outcomes in ventilated human patients [31,32,33]. The MHV1-infected mice develop clinical symptoms and pathological features similar to those in severely ill COVID-19 patients, including high levels of pulmonary edema, pneumonitis, dense inflammatory infiltrates, hyaline-like membranes, and fibrin deposits, accompanied by loss of body weight and respiratory distress [41,42,43,44]. We discuss the possible mechanisms by which GABAA -R activation attenuates disease in MHV-1-infected mice

Results

Discussion

Materials and Methods