Why Do Some People Develop Serious COVID-19 Disease After Infection, While Others Only Exhibit Mild Symptoms?

Abstract

The year 2020 was a landmark year of a once-in-a-century pandemic of a novel coronavirus, SARS-CoV-2 virus, that led to a rapidly spreading coronavirus disease (COVID-19). The spectrum of disease with SARS-CoV-2 ranges from asymptomatic to mild upper respiratory illness, to moderate to severe disease with respiratory compromise to acute respiratory distress syndrome, multiorgan failure, and death. Early in the pandemic, risk factors were recognized that contributed to more severe disease, but it became evident that individuals and even young people could have severe COVID-19. As we started to understand the immunobiology of COVID-19, it became clearer that the immune responses to SARS-CoV-2 were variable, and in some cases, the excessive inflammatory response contributed to greater morbidity and mortality. In this review, we will explore some of the additional risk factors that appear to contribute to disease severity and enhance our understanding of why some individuals experience more severe COVID-19. Recent advances in genome-wide associations have identified potential candidate genes in certain populations that may modify the host immune responses leading to dysregulated host immunity. Genetic defects of the type I interferon pathway are also linked to a more clinically severe phenotype of COVID-19. Finally, dysregulation of the adaptive immune system may also play a role in the severity and complex clinical course of patients with COVID-19. A better understanding of the host immune responses to SARS-CoV-2 will hopefully lead to new treatment modalities to prevent the poor outcomes of COVID-19 in those individuals with pre-existing risk factors or genetic variants that contribute to the dysregulated host immune responses.

Figure 1

Factors contributing to the hyperinflammatory immune response in severe SARS-CoV-2 infection. SARS-CoV-2 infects alveolar epithelial cells by binding to the angiotensin converting enzyme-2 (ACE2) receptor with the help of serine protease transmembrane serine protease 2 (TMPRSS2). The virus components (nsp6, ORF6) repress type I IFN responses by inhibiting the interferon regulatory factor 3 (IRF3) translocation to the nucleus. Repression of type I IFN responses may also be the result of pre-existing type I IFN monogenic variants, immunosenescence, or autoantibodies targeting type I IFN products (IFN α2, β, ω) preventing signaling through the IFNAR1/2 receptor complex. Delayed type I IFN responses result in the release of proinflammatory cytokines and chemokines, leading to the recruitment of monocyte-derived macrophages and T cells into the lungs. Proinflammatory signaling by activated, inflammatory macrophages leads to the recruitment of neutrophils into the lungs that undergo NETosis promoting further tissue damage. T cells recruited into the lungs appear to be of the CD4+ T_h1 phenotype that promotes an inflammatory macrophage phenotype via IFN-γ signaling. In severe cases of COVID-19, humoral responses are derived from extrafollicular B cells that produce ineffective antibody responses coupled with the production of autoantibodies. This dysregulation and imbalance of the immune response leads to a hyperinflammatory state resulting in a “cytokine storm,” acute respiratory distress syndrome, and, in many cases, death.