GABA administration prevents severe illness and death following coronavirus infection in mice

Abstract

There is an urgent need for new treatments to prevent and ameliorate severe illness and death induced by SARS-CoV-2 infection in COVID-19 patients. The coronavirus mouse hepatitis virus (MHV)-1 causes pneumonitis in mice which shares many pathological characteristics with human SARS-CoV infection. Previous studies have shown that the amino acid gamma-aminobutyric acid (GABA) has anti-inflammatory effects. We tested whether oral treatment with GABA could modulate the MHV-1 induced pneumonitis in susceptible A/J mice. As expected, MHV-1-inoculated control mice became severely ill (as measured by weight loss, clinical score, and the ratio of lung weight to body weight) and >60% of them succumbed to the infection. In contrast, mice that received GABA immediately after MHV-1 inoculation became only mildly ill and all of them recovered. When GABA treatment was initiated after the appearance of illness (3 days post-MHV-1 infection), we again observed that GABA treatment significantly reduced the severity of illness and greatly increased the frequency of recovery. Therefore, the engagement of GABA receptors (GABA-Rs) prevented the MHV-1 infection-induced severe pneumonitis and death in mice. Given that GABA-R agonists, like GABA and homotaurine, are safe for human consumption, stable, inexpensive, and available worldwide, they are promising candidates to help prevent severe illness stemming from SARS-CoV-2 infection and other coronavirus strains.

GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19

“…A/J mice were inoculated intranasally with MHV-1 (5 × 10 3 PFU) and then randomized to receive plain water (controls) or water containing GABA (20 mg/mL, as in (39)) for the remainder of the study. Mice from these groups were euthanized 3 or 6 days post-infection and the virial load in their lungs was determined.…”

“…MHV-1, DBT cells, and HeLa-CECAM1 were generously provided by Dr. Stanley Perlman (University of Iowa). MHV-I virus was prepared and titered as previously described (35–39).…”

“…At 9 weeks in age, individual A/J mice were anesthetized and inoculated intranasally with 5 × 10 3 PFU MHV-1 in 50 μl cold Dulbecco’s modified Eagle’s medium (DMEM). The mice were immediately randomized and provided with plain water (controls) or water that contained GABA (20 mg/mL) as per (9, 39) for the entirety of the observation period. The mice treated with GABA on day 0 are referred to as the GABA 0 group.…”

“…The MHV-1-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 macrophage infiltrates, hyaline membranes, fibrin deposits, accompanied by loss of body weight and respiratory distress (35–38). We previously showed that GABA treatment just after MHV-1 inoculation, or after the appearance of disease symptoms, very effectively protected the mice from severe illness and death (39). Here, we report that GABA treatment also reduced viral loads and pathological findings in their lungs.…”

GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

“…Oral treatment with GABA, which activates both GABA A -Rs and GABA B -Rs, or the GABA A -R-specific agonist homotaurine, reduces autoantigen-specific Th1 and Th17 responses, enhances CD4 + and CD8 + Treg responses, downregulates antigen-presenting cell (APC) pro-inflammatory activities, and ameliorates disease in mouse models of T1D, rheumatoid arthritis, or experimental autoimmune encephalomyelitis [ 7 , 12 , 13 , 14 , 15 , 16 ]. Our recent studies indicate that GABA treatment can also limit pulmonary inflammation in a mouse model of COVID-19 and thereby greatly reduce disease severity and death rates [ 17 ].…”