Polarised human alveolar epithelia enable identification of dichloroacetate as an effective drug against respiratory viruses

Respiratory viral infections are a significant cause of morbidity and mortality worldwide. The COVID-19 pandemic has highlighted the lack of chemotherapeutic tools available for fighting emerging viruses and the need to focus on preclinical models that better recapitulate human disease. We performed a comparative analysis of inhibitors of the PI3K/AKT/mTOR pathway, which is involved in virus-induced metabolic reprogramming, since strategies aimed at identifying cellular targets could serve to combat diverse viruses and hamper the development of resistance. Tests were performed in two human cell lines, MRC5 lung fibroblasts and Huh7 hepatoma cells, and the results showed that the inhibitors had markedly different effects on energy metabolism and antiviral activity. Thus, dichloroacetate (DCA) has potent antiviral activity against HCoV-229E in MRC5 cells but not in Huh7 cells, suggesting that the screening model is more critical than previously assumed. DCA was then tested in polarized human alveolar epithelia in air-liquid interface, a 3D model used to study respiratory infections. DCA reduced the viral progeny of HCoV-229E, SARS-CoV-2 and respiratory syncytial virus by 2-3 orders of magnitude, and it was effective even when applied once infection had been established. Although DCA has previously been shown to be effective against other viruses, suggesting that it could be a broad-spectrum antiviral, our experiments reinforce the need to use physiologically appropriate disease models to screen antiviral compound.