Immunomodulation as a Potent COVID-19 Pharmacotherapy: Past, Present and Future

Abstract

In the first year of its appearance, the 2019 coronavirus disease (COVID-19) has affected more than 150 million individuals and killed 3 million people worldwide. The pandemic has also triggered numerous global initiatives to tackle the newly emerging disease, including the development of SARS-CoV-2 vaccines and the attempt to discover potential pharmacological therapies. Nonetheless, despite the success of SARS-CoV-2 vaccine development, COVID-19 therapy remains challenging. Several repurposed drugs that were documented to be useful in small clinical trials have been shown to be ineffective in larger studies. Additionally, the pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed. Here, we reviewed the roles of immunomodulation as potential COVID-19 pharmacological modalities based on the existing data and proposed several new immunologic targets to be tested in the foreseeable future.

Keywords: COVID-19; coronavirus; drug repurposing; immune system; immunology; immunomodulation; pharmacotherapy.

Figure 1

The entry process of SARS-CoV-2 into alveolar epithelial cells, immune response activation and druggable immunologic targets in COVID-19. The SARS-CoV-2 enters the infected person via the respiratory tract and attaches to the ACE2 receptors in type-2 alveolar cells of the lungs. It subsequently activates the retinoic acid inducible gene-(RIG) I-like receptors (RLRs), which play an essential role in the activation of antiviral immune responses. Together with the intrinsic response to the viral particles, they induce hyperactive inflammatory response, marked by the activation of proinflammatory cytokines-releasing cells. Several immunologic targets were identified to have an important role in the COVID-19-mediated immune dysregulation, therefore some pharmacological agents are repurposed to reduce the COVID-19-induced hyperinflammation and to prevent the viral entry and replications.

Figure 2

The phases of COVID-19. The COVID-19 can be divided into 3 stadiums: the early infection, the pulmonary and the hyperinflammation stages. In the early infection, the viral load (purple line in the blue zone) starts to increase and at some points, it begins to activate the host immune response (red zone). While the disease progresses into a more severe state, the proinflammatory cytokines build up and start to form antibody against the virus. When the disease is not promptly treated, COVID-19 may fall into the hyperinflammation stage, multiorgan failure and death.