key: cord-0817457-lzs13mq2
authors: Poland, Gregory A.; Bass, Jessica; Goldstein, Mark R.
title: SARS-CoV-2 Infections: An ACE in the Hole and Systems Biology Studies – a Research Agenda
date: 2020-07-02
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.06.044
sha: d1b48d8413ac3a592462a5f917f95630ff335b35
doc_id: 817457
cord_uid: lzs13mq2

nan

million identified cases. Of considerable interest has been the evolving information regarding the differential morbidity and mortality caused by this novel virus. Investigators from China have published data suggesting the population-level case-fatality rate (CFR) in Wuhan was in the 2-4% range, while outside of Wuhan, but within China, it was in the 1% range. Even more interesting is that outside of China, the CFR has been generally lower-though markedly higher in Italy and among African-Americans. Why these differences?

The answers to such questions may be critical in informing prevention and both antiviral and candidate vaccine approaches. SARS-CoV-2 uses the ACE2 receptor to enter cells.

The ACE2 gene encodes the angiotensin-converting enzyme-2, and it is also the receptor for the SARS-coronavirus (SARS-CoV) and the seasonal human coronavirus NL63. This receptor is distributed across multiple organs and tissues, most notably in lymphocytes, type II alveolar cells (AT2) of the lung, and upper airway mucosa. It is also more highly concentrated within type II alveolar respiratory epithelial cells and ACE2 receptor density may be higher in Asians than in other races-though much more research is needed. In one study, East Asian populations were found to have higher rates of variants associated with higher ACE2 tissue expression, suggesting the possibility of differential susceptibility. 1 In another study, no significant differences in ACE2 gene expression were found among different racial, age, or gender groups, but significantly higher ACE2 gene expression was observed in tissue samples from smokers compared to non-smoker samples. 2 China, in particular, has high smoking rates among men. In addition, cigarette smoking appears to up-regulate ACE2 expression, potentially magnifying the risk of massive infection and, potentially, death. In addition, SARS-CoV and SARS-CoV-2 viruses require spike (S) protein priming in order to efficiently infect host mammalian cells. One report demonstrates that blocking of the serine protease TMPRSS2 abrogates SARS-CoV-2 infection of multiple cell lines. Finally, the common use of antihypertensives should also be further investigated in the pathophysiology of SARS-CoV-2 infections given conflicting reports of both increasing susceptibility and decreasing mortality due to COVID-19; however, no changes in medication use for hypertension are currently recommended.

There has been a well-documented increase in both morbidity and mortality of COVID-19 in patients with underlying hypertension, obesity, vascular disease, and diabetes mellitus even when compared against patients with underlying structural lung disease. In a small, early study, it was noted that patients with diabetes, hypertension, and CV disease had more severe disease and higher risk for hospitalization with ICU-level care, well above those with COPD or malignancy. 3 A second study showed that, of 99 patients admitted to Wuhan Junyintan Hospital from January 1-20, 2020, with COVID-19 pneumonia, 40% had underlying cardiovascular and cerebrovascular disease, followed by 13% with endocrine system disease.

Again, only 1% of patients had a past medical history of respiratory system disease. 4 A third report consisted of 129 COVID-19-positive patients who were epidemiologically linked to an LTAC facility in the state of Washington from February 27-March 9, 2020. The pattern continued with 44.6% of patients having underlying hypertension, 39.2% having cardiac disease, followed by 27.7% with renal disease, and 26.2% with DM. Those with pulmonary disease, malignancy, or who were immunocompromised made up 23.1%, 8.5%, and 6.2%, respectively. 5 The reasons for these consistencies currently remains unclear. One commonality that is shared among hypertension, cardiovascular disease, and diabetes mellitus is the use of ACEs and ARBs as a first-line therapy. If a clear link could be defined, either in terms of risk, no effect, or protection, between renin-angiotensin-aldosterone system (RAAS) inhibitors, specifically ARBs, and COVID-19 progression, then ARBs could serve as a modifiable risk factor.

Interest first arose in RAAS inhibitors because of the virus's uptake by ACE2 receptors. ARBs in particular are known to increase plasma levels of angiotensin II, which acts as a substrate for ACE2. This has been theorized to significantly upregulate ACE2 expression, potentially allowing for increased viral entry and thus worsening disease course. 6 A contradictory school of thought, however, examines the organ-protective role of ACE2, which has been shown to protect mice from severe acute lung injury induced by acid aspiration or sepsis. 7 Regarding SARS-CoV-2, ACE2 expression is sharply downregulated shortly after viral uptake, which then leads to a surge in angiotensin II activity. This activity has been theorized to contribute to the organ injury seen in COVID-19. 8 It has also been hypothesized that treatment with recombinant ACE2 could protect from development of severe acute lung injury in such scenarios.

Given the complexity and intricacies of the renin-angiotensin-aldosterone system and the seemingly conflicting information available, further independent research is certainly needed in order to better guide clinicians and patients. To date, there has been no large study analysis of these risk factors that has been adjusted for confounding variables. At present, multiple organizations such as the Council on Hypertension of the European Society of Cardiology, 9 4. Here in the United States, a phase II mRNA vaccine study is in progress. Data from such studies must be quickly made available to those of us developing candidate vaccines, as they may alter or inform other vaccine approaches. Concern exists over "S-only" vaccine approaches given the possibility of viral escape mutant, particularly if this virus evolves into a recurring seasonal infection. 11 5. It is likely that different vaccine approaches will be necessary based on factors such as age, medical condition, and perhaps previous infection. Many questions remain to be answered; chief among them being the concern of antibody-enhanced or vaccineenhanced disease occurring. This is particularly important given the preclinical animal studies of SARS vaccines that demonstrated Th2 hypersensitivity pulmonary immunopathology and hepatitis-like abnormalities after vaccination and wild virus challenge.

Research funding for antiviral and vaccine development must continue, even if and when this pandemic abates. We have now witnessed the introduction of three novel coronaviruses in the last 18 years. Multiple vaccine candidates were developed during the SARS-CoV-1 epidemic, yet not one of those progressed past phase I trials. We could have known more, we could have been better prepared, we could have had a safe and efficacious vaccine … but funding agencies and organizations globally failed to take the necessary action and ensure adequate research funding for such efforts. Research must progress past the normal human attention span of the events we are once again witnessing. To do otherwise is the height of folly. Perhaps George Bernard Shaw was right, "the thing we learn from history is that men fail to learn from history." Can't we do better together?

Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

Tobacco-Use Disparity in Gene Expression of ACE2, the Receptor of 2019-nCov

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

COVID-19 in a Long-Term Care Facility

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers

HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19

Tortoises, hares, and vaccines: A cautionary note for SARS-CoV-2 vaccine development