Therapeutic Approaches for COVID-19 Based on the Dynamics of Interferon-mediated Immune Responses

Abstract

As the outbreak of COVID-19 has accelerated, an urgent need for finding strategies to combat the virus is growing. Thus, gaining more knowledge on the pathogenicity mechanism of SARS-CoV-2, the causing agent of COVID-19, and its interaction with the immune system is of utmost importance. Although this novel virus is not well known yet, its structural and genetic similarity with SARS-CoV as well as the comparable pattern of age-mortality relations suggest that the previous findings on SARS can be applicable for COVID-19. Therefore, a systems biology study was conducted to investigate the underlying mechanism for the differences in the age-specific mortality of SARS and the most important signaling pathways activated by the virus. The results were then validated through a literature review on COVID-19 and the other closely related viruses, SARS and MERS. Interferons have shown to possess a crucial role in the defense against coronavirus diseases. The virus can impede the interferon induction in humans. Moreover, STAT1, a key protein in the interferon mediated immune response, is antagonized by the virus. This could explain the increased response threshold of immune cells to IFNs during CoV infections. A vivid correlation between the innate immune response threshold and the fatality rates in COVID-19 can be found. Differences in the dynamics of the interferons-related innate immune responses in children, adults and elderly may explain the reported fatality rates. The increased mortality rates in the elderly can be explained by the higher threshold of interferon-mediated immune responses. Earlier induction of interferons in children and their less developed immune system could be the reason behind their zero or near to zero fatality rate. Administration of interferon-inducing agents, such as Poly (ICLC), could reduce the mortality of SARS at the very early stages of the disease. Adding interferon-γ to an interferon-I, as a synergistic combination therapy, might maximize the benefits.At the later stages of the disease, however, the balance of the immune reactions would be disrupted and the responses would shift toward immnopathogenic over-reactions and probably cytokine storm. Moderating the activity of the immune system and supportive care in such conditions might be the optimum approach.

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