Potentials of Interferons and Hydroxychloroquine for the Prophylaxis and Early Treatment of COVID-19

Yang, Alexander; Guduguntla, Lakshmi S.; Yang, Bing

The symptoms of the COVID-19 range from asymptomatic or mild disease to severe disease that results in acute respiratory distress syndrome (ARDS) and eventually death. Understanding the molecular mechanisms responsible for the progression from mild to severe disease is the key to decreasing the mortality of COVID-19. Compared to mild cases, severe cases of the COVID-19 have decreased interferon (IFN) α, β, λ production. Type I (IFN α/β) and III IFNs (λ) work coordinately to induce inhibition of viral reproduction through the stimulation of interferon stimulated genes (ISGs). Failure to mount an IFN response leads to suboptimal activation of adaptive immune response and increased viral load. The increased viral load causes severe tissue damage, inducing a late wave of IFNs and an exacerbated inflammatory response. There are two known risk factors associated with severe disease- obesity and aging. Both lead to the activation of inflammasome NLRP3, which stimulates transcription factor NFκB and the production of inflammatory cytokines. Type I IFNs inhibit activation of NRLP3. Taken together, an early deficient IFN response and the following hyperinflammatory state are the hallmarks of severe COVID-19. This suggests that both type I and III IFNs could potentially be beneficial as prophylaxis and treatment of COVID-19 at the early stage of infection. Indeed, clinical studies have shown benefit of IFN Is, and there are ongoing trials testing type III IFNs for the treatment of COVID-19. Another strategy is to use hydroxychloroquine (HCQ) to inhibit the viral entry into the cells. Our reanalysis of the results from two randomized clinical trials (RCTs) has concluded that use of HCQ is beneficial in postexposure prophylaxis. These two strategies can have great potential in the current pandemic of COVID-19.