Harnessing the Immune System to Overcome Cytokine Storm and Reduce Viral Load in COVID-19: A Review of the Phases of Illness and Therapeutic Agents

Background: Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Its high infectivity rate, associated cytokine storm, and progressive lung injury make COVID-19 a public health nightmare. We reviewed 200 out of 250 articles on PubMed published between January 1st, 2000 to March 30, 2020, excluding any articles focusing on the pediatric or obstetric population. We focused on virus-host interactions and immunological mechanisms responsible for associated CRS. Based on our review, we identified three main phases of active infection. In phase one, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early interferon (IFN) response allowing unchecked viral replication. Phase two is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase three, characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Phase three may be followed by a recovery phase with production of specific antiviral antibodies. This response is highly associated with mortality. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α. This may be followed by a recovery phase with antibodies against the virus. We review existing data about virus-host interactions, as well as key immunological mechanisms responsible for associated cytokine storm. Conclusion: Developing effective therapeutic agents will require understanding of virus-host interactions and mechanisms of virus-associated immune dysregulation. Despite rapidly emerging information about SARS-CoV-2, there are still significant gaps in understanding of its pathogenesis, including the mechanisms of inducing adult respiratory distress syndrome (ARDS) and cytokine release syndrome (CRS). A better understanding of the pathophysiology and immune dysregulation associated with CRS and ARDS in severe COVID-19 is imperative to predict the success of potential drug targets for possible effective therapy of COVID-19, which have also been reviewed in this article.