OPINION

published: 23 April 2020

doi: 10.3389/fped.2020.00206

COVID-19 Infection and Circulating

ACE2 Levels: Protective Role in
Women and Children
Elena Ciaglia 1*, Carmine Vecchione 1,2 and Annibale Alessandro Puca 1,3
1
Department of Medicine, Surgery and Dentistry Scuola Medica Salernitana, University of Salerno, Salerno, Italy,
2
Department of Vascular Physiopathology, IRCCS Neuromed, Pozzilli, Italy, 3 Cardiovascular Research Unit, IRCCS
MultiMedica, Milan, Italy

Keywords: infection-immunology, biomarker, screening tools, SARS-CoV, ACE-angiotensin-converting enzyme

It has been reported that angiotensin-converting enzyme 2 (ACE2) is the main host cell receptor
of human pathogenic coronaviruses [severe acute respiratory syndrome coronavirus (SARS-CoV),
HCoV-NL63, and SARSCoV-2 (COVID-19)], and it plays a crucial role in the entry of virus into the
cell to cause the final infection (1). Wrapp and colleagues recently provided the Cryo-EM structure
of the virus spike protein, the known ligand for ACE2, and documented a 10 to 20-fold higher
affinity of ACE2 for SARS-CoV-2 compared to previous SARS-CoV (2).
ACE2 is mainly expressed by epithelial cells of the lung, intestine, kidney, and blood vessels (3).
This may explain the high incidence of pneumonia and bronchitis in those with a severe COVID-
19 infection. A recent study showed that ACE2 is also highly expressed on the mucosa of the oral
cavity, granting the virus easy access to a new susceptible host (4).
While it has been consolidated that human pathogenic coronaviruses use this same keyhole to
enter cells (4, 5), new incoming evidence might suggest that we look at ACE2 as an ally in the global
Edited by:
Christoph Aebi,
fight against COVID-19 fighting rather than an obvious molecular target.
University Children’s Hospital Seen its role as in vivo SARS receptor, ACE2 expression was shown to correlate with
Bern, Switzerland susceptibility to SARS-CoV spike protein (SARS-S)-driven entry (6, 7), and pathologic alterations
Reviewed by: in lungs were significantly reduced in ACE2 mutant mice. As a consequence, the systemic treatment
Arne Simon, with recombinant ACE2 was able to reduce lung injury (8).
Saarland University Hospital, Germany On the other hand, ACE2 receptor abundance goes down in the elderly in all these tissues, but,
*Correspondence: counterintuitively, this might place them at a greater risk of severe illness. So, what of the role of
Elena Ciaglia ACE2 in new COVID-19 infection?
[email protected] The explanation behind this apparent paradox might lie in the post-translational events
regulating protein levels and their balance between the membrane-bound and soluble forms.
Specialty section: Indeed, ACE2 can undergo an ADAM17 (a disintegrin and metalloproteinase 17)-mediated
This article was submitted to “shedding” from endothelial cells, resulting in the release of the ectodomain with a catalytic and
Pediatric Infectious Diseases, bioactive power into the circulation (9).
a section of the journal
Accordingly, in 2014, study scientists found that the circulating ACE2 enzyme offers protection
Frontiers in Pediatrics
against influenza A (H7N9) virus-induced acute lung injury (10). Some patients with better
Received: 26 March 2020 outcomes have exhibited higher levels of the protein in their sera; meanwhile, turning off the
Accepted: 06 April 2020
gene for ACE2 led to severe lung damage in mice infected with H5N1, while treating mice with
Published: 23 April 2020
human ACE2 dampened lung injury (10). Furthermore, a single dose of recombinant human ACE2
Citation:
(GSK2586881; 0.2 mg·kg−1 or 0.4 mg·kg−1 i.v., NCT01884051) has been shown to demonstrate
Ciaglia E, Vecchione C and Puca AA
(2020) COVID-19 Infection and
haemodynamic benefits in pulmonary arterial hypertension both in a preclinical and clinical
Circulating ACE2 Levels: Protective setting (11).
Role in Women and Children. Some previous studies suggested that genetic variants in the ACE2 gene might have a potential
Front. Pediatr. 8:206. to affect ACE2 level in the human body. In the Leeds Family Study, ACE, ACE2, and neutral
doi: 10.3389/fped.2020.00206 endopeptidase (NEP) activities were measured in plasma from 534 subjects, and it was indicated

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Ciaglia et al. Soluble ACE2 in COVID-19 Patients

that up to 67% of the phenotypic variation in circulating contrary to adults, there was no significant gender difference
ACE2 could be accounted for by genetic factors (12). Among in young patients (20); this is probably due to the influence
different polymorphisms, it has been speculated that ACE2 of the degree of sexual maturation in children and adolescents.
rs2106809 might exhibit primary effects on the ACE2 levels. Indeed, not only estradiol, via the ER, is a known modulator
The circulating ACE2 levels tend to be greater in CC or of the ACE/ACE2 and AT1/AT2 receptor, but ACE is also
CT genotype compared with that in the TT genotype. One connected to male reproduction. Catalytic activity of testis
possible mechanism can be mediated by microRNA, which could ACE contains only the carboxy-terminal domain of ACE,
modulate endothelial function via translational repression and/or which has exhibited unknown effects on a substrate other than
posttranscriptional degradation. angiotensin I (21).
Furthermore, several significant differences in the frequency The reason why the disease is less robust in extremely young
of distribution of ACE2 variants among different racial and animals or humans than in older ones may therefore lie not
ethnic lines have been described. A recent single-cell RNA- only in some “cross-immunity” offered by previous infection to
sequencing (RNA-seq) analysis indicated that Asian males may “common cold” viruses experienced by children, nor does it lie
have a higher expression of tissue ACE2 (13). In another case exclusively in a powerful immune system that, as a result, is not
control study conducted in the north eastern Chinese Han affected by the senescence process; it is probably also affected
population, the serum ACE2 activity negatively correlated with by an unique ACE2 plasma profile that need to be dissected.
body mass index (BMI), pulse pressure, and estrogen levels By a buffering effect, and much like neutralizing antibodies,
in female EH (essential hypertension) patients (14). These soluble ACE2 may help children and asymptomatic people to
observations point both to a cardiovascular protective effect better counteract virus spreading to a cell target. On one hand,
of circulating levels of ACE2 and simultaneously prove that this could help them to contain infection. On the other hand,
estrogens participate in the upregulation of ACE2 expression and this could also let these carriers be an important reservoir of
activity levels (15). This might explain the relative protection circulating virus, and so this deserve much of our attention in
of female vs. male in COVID-19 infection. Taken together, this the near future.
evidence seem to indicate that the putative sex predisposition to Answering questions about coronavirus in children and in
COVID-19, with men being more susceptible, might be reflective people who develop less severe symptoms could reverberate
of a peculiar ACE plasma profile. well-beyond this escaper population. It could shed light on
A putative trend toward this kind of association was also seen the reasons why some patients are most at risk and why
in children. Children generally have higher levels of ACE2 than others could better counteract the spreading of the virus.
adults (16). For example, ACE levels in children (6 months to 17 Furthermore, studying the physiology of those who are less
years of age) are 13–100 U/l compared with 9–67 U/l in adults affected could be of help in the development of treatment and
when using an FAPGG-based enzymatic activity assay. Of note is a vaccine.
the fact that children with confirmed COVID-19 have generally In the last years, the ACE2 activity level has been a
presented with mild symptoms. Cases of coronavirus disease potential biomarker for the variations of blood pressure,
2019 (COVID-19) among children in China have been less severe providing useful information for the prediction and prevention
than those in adults, according to a new study. In a study of 1,099 of cardiac dysfunction. Now, circulating level of ACE2 may
patients in China, just 0.9 percent of the confirmed cases were have prognostic effect in monitoring COVID-infection, and
under the age of nine, while only 1.2 percent were between 10 the genetic analysis of ACE2 polymorphisms might be a key
and 19 years old (17). A similar phenomenon in a mouse study element of individualized care for its prevention, diagnosis,
in North Carolina was registered by Baric et al.—although SARS- and treatment. In this context, an ELISA-based accurate
CoV can replicate fairly well, younger animals are really resistant quantification of human soluble ACE2, not only in serum and
to infection in terms of the disease. When older animals were EDTA plasma but also in more accessible human body fluids
tested, the severity of SARS illnesses rose (18). (e.g., saliva, urine, tears, and milk), should be proposed as a
In our opinion, the explanation for the correlation between first rapid test screening. To be noted, a standardized protocol
age and COVID-19 disease severity might be related not only for sampling, transport, and storage before its dosage, must
to the immune decline of an aged immune system (termed be rigorously followed to ensure the accuracy and reliability
immunesenescence) but also to a peculiar ACE plasma profile of inter- and intra-individual quantitation during the course
that may characterize children from birth. Indeed in mid to of pathology. Furthermore, correct tests should be carried
late pregnancy in women, an increase in urine and plasma out in simultaneously in aged-matched healthy volunteers
levels of ACE2 were found as well as an increase in local for comparisons. If the current hypothesis is correct, ACE2
placental/uterine production and activity of ACE2, suggesting a determination, by both ELISA and more sensitive HPLC-MS
systemic hemodynamic role in the enhancement of placental– methods, may represent a less extensive and time-consuming
fetal blood flow and rapid fetal growth (19). means to monitor COVID-19 infection both at pre-clinical and
ACE can pass through the placenta, enabling the mother to clinical levels.
transfer to baby her immunity and other kinds of protective With the rapid progress that has been made with diagnostic
soluble factors. reagents (e.g., nucleic acid and IgM or IgG detection or
Epidemiological characteristics and transmission patterns both), drug repurposing (e.g., remdesivir and chloroquine),
of pediatric patients with COVID-19 in China revealed that, immunotherapeutic approaches (e.g., Tocilizumab), and vaccine

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Ciaglia et al. Soluble ACE2 in COVID-19 Patients

production as a consequence of the outbreak of novel COVID- AUTHOR CONTRIBUTIONS

19, we thought that it is timely to shed light on the
putative link between circulating ACE2 and disease severity. All authors listed have made a substantial, direct and intellectual
Indeed, as discussed, it may represent a rapidly emerging contribution to the work, and approved it for publication.
field of study for therapeutic intervention in the context of
COVID-19 infection. FUNDING
Concerning this, as Penniger JM and colleagues
declared in the last days, the availability of recombinant This work was supported by: research funding from
ACE2 (rhACE2; APN01, GSK2586881), its safety profile, Cariplo Foundation (no. 2016-0874) to AP and CV;
and the anti-inflammatory effects (mainly linked to its PRIN-20157ATSLF_009 to AP and CV; EC was supported
ability to reduce IL-6 plasma levels) will be the impetus by a fellowship from Fondazione Umberto Veronesi
to rapidly launch a pilot trial of rhACE2 as a hopeful (FUV 2019cod.2198). Funding/financial support was obtained
treatment option for patients with severe COVID-19 also from the Italian Ministry of Health, RicercaCorrente to the
(clinical trials.gov#NCT04287686). IRCCS MultiMedica.

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