Summary and Conclusions
The COVID-19 pandemic has sparked an urgent search for effective therapeutics, with little clear success at the time we have prepared this article (early April, 2020). Targeting the RAS pathway has received limited attention even though it is an important component of COVID-19 pathobiology with implications for therapeutics that could ameliorate tissue injury, disease progression and improve morbidity and mortality. A key reason for the limited attention on the RAS system as a therapeutic target may stem from the lack of mechanistic insight regarding the potential benefit of targeting this pathway.
To address this gap, we propose an overriding hypothesis:imbalance of ACE1- and ACE2-mediated signaling as a primary driver of tissue pathobiology in COVID-19, impacting the phenotypes of multiple interacting cell types in infected tissue, leading to feedback loops that promote inflammation and injury . Tissue damage from the infection is a consequence of enhanced ANG II/AGTR1 signaling and decreased signaling by ANG (1-7) and perhaps other ACE2-derived peptides. In the lungs and heart (Figures 3, 5 ), the imbalance in the RAS pathway and positive feedback loops can establish a vicious cycle of events mediated by communication among cell types that produce COVID-19 pathology. Similar mechanisms may also occur in other organs.
Numerous studies and findings corroborate this hypothesis, including results from animal models, clinical data in humans and in-vitro findings with human and rodent cells. Moreover, it provides a parsimonious explanation for key features of the disease and for the contribution of comorbidities to adverse outcomes in COVID-19.
The hypothesis also leads to several testable predictions for COVID-19: a) susceptibility for adverse outcomes in those with specific ACE1 genotypes and perhaps other genetic variants in RAS pathway elements; b) potential for patients with a range of illnesses to have worse outcomes; c) adjusting for other clinical variables, patients administered ARBs (and perhaps ACEIs) should have improved outcomes; d) counteracting the imbalance in RAS signaling with agents discussed above should modulate clinicopathological effects of the SARS-CoV-2 virus; e) early administration of RAS-targeted agents may yield maximum benefit, preventing ALI and ARDS by mitigating the damage from the imbalance in ACE1- and ACE2-derived peptides and their signaling.
Given the severity of the COVID-19 crisis, what types of studies (besides clinical trials) might help test our hypothesis? We envisage several possibilities: a) in-vitro studies using human alveolar epithelial cells, perhaps in 3-D organoid models in co-cultures with other key cell types (e.g. fibroblasts, endothelial cells, immune cells) to determine if cellular injury by SARS-CoV-2 infection is inhibited by ACEIs/ARBs/soluble ACE2. Monteil et al., (2020) have demonstrated efficacy of recombinant ACE2 in blunting infectivity of SARS-CoV-2 in such models but more detailed analyses and further studies are needed. b) In vivo studies to test efficacy of ACEIs/ARBs/soluble ACE2 in animal models [e.g., mice, ferrets and rhesus monkeys, with preference for primate models, e.g., Sutton & Subbarao, (2015); Gretebeck & Subbarao, (2015)] of SARS-1 infection. Ferrets may be useful to assess SARS-CoV-2 infectivity but infected animals appear to have few pathological features (Shi et al., 2020); rhesus monkeys with SARS-CoV-2 infection also show signs of clinical disease (Bao et al., 2020). c) epidemiological data from COVID-19 patients to define associations between ACEI/ARB use/dose and disease severity/mortality. Certain data of this type have been obtained (Liu et al., 2020) but more are needed, especially because of confounding factors in such analyses, including comorbidities relevant to COVID-19. A multi-country database that assessed usage of ARBs and ACEIs prior to hospital admission with clinical outcomes from COVID-19 might be very helpful for such analyses and to define possible differences from patients in different countries.
The hypothesis thus implies that those being treated for approved indications with ACEIs and ARBS should maintain their use of these drugs and in addition, that those drugs may have therapeutic utility in treating patients who develop COVID-19, in particular those most vulnerable to this viral infection (e.g., those >70 years old and/or with comorbidities). ACEIs and ARBs have well known safety profiles, making these drugs well-suited for repurposing. In addition, a rationale exists for testing the possible therapeutic effects of soluble ACE2 or perhaps ACE2 peptides. The current and likely future challenge of treating seriously ill COVID-19 patients argues for aggressive approaches. We urge that these approaches include ones that seek to restore ACE1/ACE2 imbalance.