We established a murine hepatitis virus-1 (MHV-1) coronavirus model, to study disease mechanisms of Covid-19 (Viruses, 2021). With the goal of creating a therapeutic for pregnancy, using advanced imaging techniques, computational modeling, molecular dynamics and spectroscopy, we invented and tested a small peptide, SPIKENET (SPK) with high binding affinity to spike protein of MHV-1. SPK significantly reduced acute (7 days) and long term (1 year) consequences (mortality, pathology, and weight loss) (Front. Pharmacol, 2022, Mol Neurobiol 2022). Since we discovered the role of aquaporins (AQP) water channels in edema development, and that SPK reversed such an effect, we examined the molecular events in the development of lung and brain edema. Using our MHV-1 model (non-pregnant), we examined the involvement of factors known to modulate volume changes in lung and brain, namely [N-Methyl-D-Aspartate receptors (NMDAR1/2), and surfactant A]. Mice were inoculated with 5000 PFU intranasally, and divided into 5 groups (n=5/group): control (no infusion); control with Dulbecco’s Modified Eagle Medium; MHV-1; SPK 5mg/kg/d subcutaneous (s.c.) on days 2,4,6; MHV-1 plus SPK 5mg/kg/d s.c. on days 2,4,6. Mice were sacrificed 7 days post inoculation. Data were subjected to ANOVA and Tukey’s test with a level of significance p< 0.05. Lung NMDAR1/2 levels are increased (160.3 and 124.6%, respectively, p< 0.05) (Fig. 1). Similarly, brain NMDAR1 levels are increased (109.4%, p< 0.05), while brain NMDAR2 level are decreased (42.8%, p< 0.05) (Fig. 1). Surfactant A level decreased in the brain post-infection (57.4%, p< 0.05) while its level increased in the lung after infection (187.2%, p< 0.05) (Fig. 2). SPK normalized NMDAR1/2 and surfactant A levels in lung and brain. We report for the first time that lung and brain NMDA receptors and surfactant A are involved in the development of COVID-19 disease progression. Our invention, SPIKENET, abrogates these critical events, and together with our AQP findings, strongly suggest the potential therapeutic benefit of SPK in counteracting COVID-19.View Large Image Figure ViewerDownload Hi-res image Download (PPT)