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).
- 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.
- 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.
- 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.
- 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.
- 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.