1HIV/STI Unit, Institute of Tropical Medicine,
Antwerp, Belgium; 2Division of Infectious Diseases and
HIV Medicine, University of Cape Town, Anzio Road, Observatory 7700,
South Africa;
*Corresponding author. HIV/STI Unit, Institute of Tropical Medicine,
Antwerp, 2000, Belgium. Tel: +32 3 2480796; Fax: +32 3 2480831; E-mail:
ckenyon@itg.be
Word Count: 421
Keywords: Angiotensin-converting enzyme; exercise; ACE2;
SARS-CoV-2; COVID-19 severity
Dear Editors,
Sriram et al., recently argued that an imbalance between angiotensin
converting enzyme-1 (ACE1) and ACE2 explained why only a small
proportion of those infected with SARS-CoV-2 develop severe COVID-19
disease (Sriram & Insel, 2020). Their theory provides a parsimonious
explanation for why all around the world severe COVID-19 is closely
linked to older ages as well as certain comorbidities such as
hypertension, diabetes, obesity and heart failure but not others such as
asthma, COPD and HIV (Sriram & Insel, 2020). Older age as well as
hypertension, diabetes, obesity and heart failure are all associated
with a relative upregulation of the pro-inflammatory ACE1/angiotensin
II/angiotensin 2 receptor 1-axis and downregulation of the
anti-inflammatory ACE2/angiotensin (1-7)/Mas axis. This imbalance is
aggravated by SARS-CoV-2 which uses ACE2 for cell entry and results in
downregulation of ACE2 expression in alveolar cells and elsewhere.
Individuals with this ACE1 proinflammatory, pro-apoptotic, pro-fibrotic
bias are more likely to respond to COVID-19 with an untargeted,
hyperinflammatory response that can progress to an acute respiratory
distress syndrome-type illness before their adaptive immune system can
adequately respond to the viral infection (Sriram & Insel, 2020).
Individuals with a balanced ACE1/ACE2 system by contrast do not develop
this hyperinflammatory response and are able to mount an effective
immune response and eradicate the virus with few or no symptoms.
Whilst this is likely a simplification of the pathophysiology of severe
COVID-19, it does potentially offer a cheap, low risk strategy for whole
populations to reduce their risk of severe COVID-19 – exercise. A
number of studies in a range of animals, including humans, have found
that exercise results in a number of health and metabolic benefits
including upregulating ACE2 and downregulating ACE1
(Echeverria-Rodriguez, Gallardo-Ortiz, Del Valle-Mondragon, &
Villalobos-Molina, 2020; Magalhaes et al., 2020). One study for example
estimated that every hour run prolongs one’s life by 7 hours (Lee et
al., 2017). These considerations led us to add to the hypothesis of
Sriram et al., that the promotion of exercise, particularly in those at
risk for severe COVID-19 will reduce the probability of them developing
severe COVID-19. The available evidence is that both moderate- and high
intensity aerobic exercise result in the rapid upregulation of the ACE2
versus ACE1 axis (Magalhaes et al., 2020). Randomized controlled trials
in animal models of COVID-19 (Chan et al., 2020) or high-risk groups of
humans would be required to test if this is protective against severe
COVID-19 as well as to ascertain what the optimal training regimens for
specific risk profiles would be. Pending these studies, a reasonable
argument could made that the health benefits of exercise in these risk
groups are so well established that this novel hypothesis could still be
shared with target groups (Lee et al., 2017).