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SARS-CoV-2 Infections: An ACE in the Hole and Systems Biology Studies—a Research Agenda

      As of the time of this writing, severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 has involved nearly every country, with almost 6 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 that the population-level case fatality rate in Wuhan was in the 2% to 4% range, whereas outside Wuhan but within China, it was in the 1% range. Even more interesting is that outside China, the case fatality rate has been generally lower—although 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. The SARS-CoV-2 uses the angiotensin I–converting enzyme 2 (ACE2) receptor to enter cells. The ACE2 gene encodes the ACE2, and it is also the receptor for the SARS-CoV and the seasonal human CoV NL63. This receptor is distributed across multiple organs and tissues, most notably in lymphocytes, type II alveolar cells 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—although much more research is needed for confirmation. 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.
      • Cao Y.
      • Li L.
      • Feng Z.
      • et al.
      Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations.
      In another study, no significant differences in ACE2 gene expression were found among different racial, age, or sex groups, but significantly higher ACE2 gene expression was observed in tissue samples from smokers compared with nonsmoker samples.
      • Cai G.
      Tobacco-use disparity in gene expression of ACE2, the receptor of 2019-nCov.
      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 found that blocking of the serine protease TMPRSS2 abrogates SARS-CoV-2 infection of multiple cell lines.
      • Hoffmann M.
      • Kleine-Weber H.
      • Schroeder S.
      • Krüger N.
      • Herrler T.
      • Erichsen S.
      • et al.
      SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.
      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 coronavirus disease 2019 (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 associated with COVID-19 in patients with underlying hypertension, obesity, vascular disease, and diabetes mellitus even when compared with patients who have underlying structural lung disease. In a small, early study, it was noted that patients with diabetes, hypertension, and cardiovascular disease had more severe disease and higher risk for hospitalization with intensive care unit–level care, well above those with chronic obstructive pulmonary disease or malignancy.
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China (published correction appears in Lancet. 2020;395(10223):496).
      A second study found that among 99 patients admitted to Wuhan Jinyintan Hospital from January 1 through January 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 medical history of respiratory system disease.
      • Chen N.
      • Zhou M.
      • Dong X.
      • et al.
      Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.
      A third report described 129 COVID-19–positive patients who were epidemiologically linked to a long-term acute care facility in the state of Washington from February 27 through March 9, 2020. The pattern continued with 44.6% of patients having underlying hypertension, 39.2% having cardiac disease, 27.7% with renal disease, and 26.2% with diabetes mellitus. Those with pulmonary disease, malignancy, or immunocompromise made up 23.1%, 8.5%, and 6.2%, respectively.
      • McMichael T.M.
      • Clark S.
      • Pogosjans S.
      • et al.
      Public Health – Seattle & King County, EvergreenHealth, and CDC COVID-19 Investigation Team
      COVID-19 in a long-term care facility - King County, Washington, February 27-March 9, 2020.
      The reasons for these consistencies currently remains unclear. One commonality that is shared among hypertension, cardiovascular disease, and diabetes mellitus is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (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. Angiotensin receptor blockers, in particular, are known to increase plasma levels of angiotensin II, which acts as a substrate for ACE2. This factor has been theorized to significantly up-regulate ACE2 expression, potentially allowing for increased viral entry and thus worsening disease course.
      • Esler M.
      • Esler D.
      Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?.
      A contradictory school of thought, however, examines the organ-protective role of ACE2, which has been reported to protect mice from severe acute lung injury induced by acid aspiration or sepsis.
      • Imai Y.
      • Kuba K.
      • Rao S.
      • et al.
      Angiotensin-converting enzyme 2 protects from severe acute lung failure.
      Regarding SARS-CoV-2, ACE2 expression is sharply down-regulated 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.
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.J.V.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19.
      It has also been hypothesized that treatment with recombinant ACE2 could protect patients against development of severe acute lung injury in such scenarios.
      Given the complexity and intricacies of the RAAS 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
      European Society of Cardiology
      Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. European Society of Cardiology website.
      and the Heart Failure Society of America/American College of Cardiology/American Heart Association
      American Heart Association
      HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. American Heart Association website.
      have released statements on the topic of RAAS inhibitors and COVID-19 and agree that patients should continue their current therapies as prescribed until further clinical studies have been conducted.
      We suggest multiple lines of research as we move toward developing COVID-19 countermeasures, especially antivirals and vaccines, to SARS-CoV-2 infections:
      • 1.
        Understand if any differential rates of illness, severity, or mortality result from the use of angiotensin-converting enzyme inhibitors, ARBs, and other common antihypertensives.
      • 2.
        We need systems biology studies of SARS-CoV-2 infection in different populations, including by age, sex, and race. Although reductionist studies of individual parameters of infection and immunity can be helpful, only systems-level studies can provide a holistic look at how the immune system differentially responds to infection, new therapies, and vaccines. In turn, such information can inform new antiviral and vaccine development. Are there molecular signatures (innate, humoral, cellular) of infection or of the likelihood of mild or severe disease? Or of antiviral or vaccine rersponse?
      • 3.
        We need ongoing, high-volume sequence information on genetic variants of SARS-CoV-2 S and other structural proteins on host ACE2 receptors and on variants or isoforms of host TMPRSS2 serine proteases used to activate S protein. Such information must also be correlated with possible differential infection and clinical course outcome data.
      • 4.
        Here in the United States, a phase 2 messenger RNA 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.
        • Poland G.A.
        Tortoises, hares, and vaccines: a cautionary note for SARS-CoV-2 vaccine development [editorial].
      • 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 about the occurrence of antibody-enhanced or vaccine-enhanced disease. This issue is particularly important given the preclinical animal studies of SARS vaccines that documented helper T cell type 2 hypersensitivity pulmonary immunopathology and hepatitislike 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 3 novel coronaviruses in the past 18 years. Multiple vaccine candidates were developed during the SARS-CoV-1 epidemic, yet not one of those progressed past phase 1 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?

      References

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      Linked Article

      • In the Limelight: September 2020
        Mayo Clinic ProceedingsVol. 95Issue 9
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          This month’s feature highlights five articles on COVID-19 that appear in the current print and online issue of Mayo Clinic Proceedings. These articles are also featured on the Mayo Clinic Proceedings’ YouTube Channel ( https://youtu.be/MT3ZFDAOKYU ).
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