A GABA-receptor agonist reduces pneumonitis severity, viral load, and death rate in SARS-CoV-2-infected mice

Abstract

Gamma-aminobutyric acid (GABA) and GABA-receptors (GABA-Rs) form a major neurotransmitter system in the brain. GABA-Rs are also expressed by 1) cells of the innate and adaptive immune system and act to inhibit their inflammatory activities, and 2) lung epithelial cells and GABA-R agonists/potentiators have been observed to limit acute lung injuries. These biological properties suggest that GABA-R agonists may have potential for treating COVID-19. We previously reported that GABA-R agonist treatments protected mice from severe disease induced by infection with a lethal mouse coronavirus (MHV-1). Because MHV-1 targets different cellular receptors and is biologically distinct from SARS-CoV-2, we sought to test GABA therapy in K18-hACE2 mice which develop severe pneumonitis with high lethality following SARS-CoV-2 infection. We observed that GABA treatment initiated immediately after SARS-CoV-2 infection, or 2 days later near the peak of lung viral load, reduced pneumonitis severity and death rates in K18-hACE2 mice. GABA-treated mice had reduced lung viral loads and displayed shifts in their serum cytokine/chemokine levels that are associated with better outcomes in COVID-19 patients. Thus, GABA-R activation had multiple effects that are also desirable for the treatment of COVID-19. The protective effects of GABA against two very different beta coronaviruses (SARS-CoV-2 and MHV-1) suggest that it may provide a generalizable off-the-shelf therapy to help treat diseases induced by new SARS-CoV-2 variants and novel coronaviruses that evade immune responses and antiviral medications. GABA is inexpensive, safe for human use, and stable at room temperature, making it an attractive candidate for testing in clinical trials. We also discuss the potential of GABA-R agonists for limiting COVID-19-associated neuroinflammation.