Figure 4. ACE1/ACE2 imbalance, lung injury, and factors that determine severe pathology or mild illness. (A.) A model for the course of COVID-19 that links ACE1/ACE2 imbalance to lung injury via the RAS pathway and the protective role of the immune response. (B.) An illustration of the predicted course of COVID-19 in two settings: top : Severe pathology, in patients who lack appropriate immune response or who have prior conditions that enhance ACE1/ACE imbalance (and RAS-induced injury). The result is increased injury that overwhelms the adaptive immune response; bottom : Mild illness, in which patients lack underlying conditions and can mount an appropriate immune response, so that RAS-induced injury is less serious, an effective immune response occurs and the infection is resolved.
Early insights into the immune response to COVID-19 have been reported (To et al., 2020, Thevarajan et al., 2020 and Zhou et al., 2020) along with the proposed models of this response (Li et al., 2020; Prompetchara et al., 2020). Analysis of the immunopathology of SARS-1 and MERS (Channappanavar and Perlman, 2017) is consistent with such data and models. Prior reviews describe the importance of T cell-mediated adaptive immune response to coronaviruses, especially SARS (Channappanavar et al. 2014) and Li et al., 2009) and provided insight into roles of macrophages, dendritic cells, B cells and T cells in SARS-CoV-1 infection (Zhao et al., 2009; Yasui et al., 2014).
Based on these studies, the following framework describes the interplay between pathological—as opposed to protective– immune response and acute pulmonary injury in COVID-19, in part extrapolating from information and ideas related to SARS-CoV-1 (Channappanavar and Perlman 2017).
  1. During early stages of infection, inflammatory cells (macrophages, neutrophils and dendritic cells) infiltrate into the alveoli in response to cytokine secretion by alveolar cells. Immune infiltration is greater in subjects who experience more rapid RAS-induced injury and epithelial cell death (i.e., a more severe imbalance between ACE1 and ACE2), thereby establishing a positive feedback loop: accumulation of large numbers of inflammatory cells further promotes cell death in alveoli.
  2. Human coronaviruses express proteins that suppress the production by immune cells of interferons (IFNs), which suppress viral replication. This IFN response is exacerbated and injury is increased in conditions of ‘hyper-inflammation’ that undermine protective innate immune responses. Such hyper-inflammation is more likely to occur in conditions of escalated RAS-driven injury, due to greater ACE1/ACE2 imbalance.
  3. Seroconversion begins early, within ~5 days from the onset of symptoms, with increasing titers of IgM antibodies, and promotes an adaptive immune response, mediated by T helper cells, cytotoxic T cells and antibody production by B cells, recruited by T helper cells. Hyper-inflammation results from extensive injury that overwhelms this adaptive response, with accumulation of activated macrophages that can suppress effective antigen presentation by dendritic cells and the recruitment of T cells.
  4. In patients with mild pulmonary injury, effective recruitment of T cells leads to clearance of the virus, followed by tissue repair and restoration of homeostasis. Transition occurs from IgM to IgG antibodies. In the case of severe pathology, a vicious cycle of inflammation and cell death leads to widespread epithelial disruption and onset of pneumonia. Such patients are more vulnerable to bacterial infection with the decrease in surfactant production and loss of an intact epithelial barrier.
  5. Mild disease (with less severe RAS-driven effects) shows a progressive decline in viral loads and improvement in symptoms and signs of infection, generally by ~7 days from initial symptoms. In progressive disease (with more severe RAS-driven effects), greater pulmonary injury (perhaps with secondary pneumonia) necessitates critical care, including assisted ventilation. ARDS can develop if inflammation, cell death and infection continue. Cardiac complications may exacerbate this, especially if myocarditis and further pulmonary edema occur. The cytokine storm stemming from ARDS also has the potential to exert systemic effects, raising the risk of multiple organ failure (Pedersen & Ho, 2020).
The outcome of COVID-19 infection is thus determined by the competing actions of different elements that promote (the RAS pathway) or blunt (immune response) lung injury (Figure 4 ). In severe cases, a series of injurious effects unfold and overwhelm protective immune responses. Greater imbalance in the effects if ACE1 and ACE2 in the RAS pathway is predicted to exacerbate pathology, making it more likely that the immune response will be overcome. Factors/comorbidities that increase the ACE1/ACE2 imbalance are discussed below.