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1 These authors contributed equally to this study.
Affiliations
Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
1 These authors contributed equally to this study.
Affiliations
Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
Department of Pediatrics/Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, Chengdu 610041, China
As a counter-regulatory arm of the renin–angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury.
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The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 for human ACE2 (hACE2) largely determines the degree of clinical symptoms in those infected by SARS-CoV-2.
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Vitamin D was found to affect ACE2—the same target for SARS-CoV-2; we therefore propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 through modulating ACE2.
Abstract
A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed as having the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) is known to be expressed on type II pneumocytes. As a counter-regulatory arm of the renin–angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury.
The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 for human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have shown that regulating the ACE2/RAS system is effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor for both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.
A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) had caused 4,761,559 confirmed cases and 317,529 confirmed deaths worldwide, as of May 20, 2020 (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Many of the symptoms caused by SARS-CoV-2 are similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV), especially acute respiratory distress syndrome (ARDS) (
). ARDS is associated with increased alveolar epithelial permeability and pulmonary microvascular endothelial permeability, pulmonary edema, and pulmonary fibrosis (
). The SARS-CoV envelope-anchored spike protein has been shown to bind to the host receptor and then induce virus replication, and different structures of the SARS-CoV spike protein may bind to different target receptors (
The next big threat to global health? 2019 novel coronavirus (2019-nCoV): What advice can we give to travellers?—Interim recommendations January 2020, from the Latin-American society for Travel Medicine (SLAMVI).
Evidence for the influence of angiotensin converting enzyme-2 (ACE2) on SARS-CoV-induced ARDS
The SARS epidemic occurred in southern China and caused more than 8000 cases of infection worldwide in 2002–2003, with an approximately 10% fatality rate (
) (Figure 1). Mutations in the RBM affect the interactions of the spike protein and ACE2. For example, mutations at residues 479 and 487 of the RBM control cross-species infections and human transmission of SARS-CoV, respectively (
). Furthermore, the affinity of the spike protein receptor binding domain (RBD) for human ACE2 (hACE2) predominantly determines the degree of clinical symptoms caused by SARS-CoV (
). When Ang Ⅱ binds to the AT1a receptor it induces increased alveolar epithelial permeability and pulmonary microvascular endothelial permeability, pulmonary edema, and pulmonary fibrosis. However, the opposite effects occur when Ang Ⅱ binds to the AT2 receptor. In addition, as a counter-regulatory arm of RAS, ACE2-Ang1-7 can bind to the Mas receptor to inhibit the above process and thus protect against lung injury (
Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-kappa B signaling pathways.
). The balance of Ang Ⅱ/Ang1-7 is commonly disrupted after infection with SARS-CoV; the ratio of Ang Ⅱ/Ang1-7 is increased due to decreased expression of ACE2, which can lead to acute lung injury and ARDS (
The SARS-CoV spike protein has been shown to bind to ACE2 and induce interleukin-8 (IL-8) release from lung cells by activating activation protein 1 (AP-1) (
). Dysregulation of inflammatory cytokines may be involved in ARDS. High levels of proinflammatory cytokines, such as transforming growth factor β (TGFβ), IL-8, IL-6, tumor necrosis factor alpha (TNF-α), interferon alpha (IFN-α), IFN-β, IFN-γ, chemokine (C-C motif) ligand 3 (CCL3), CCL5, and CXCL10, have been detected in SARS-CoV infection (
Severe acute respiratory syndrome coronavirus fails to activate cytokine-mediated innate immune responses in cultured human monocyte-derived dendritic cells.
) reported that SARS-CoV-induced casein Ⅱ (CK Ⅱ)-mediated phosphorylation of the ACE2 receptor activated ERK1/2 and upregulated AP-1/CCL2, thus leading to ARDS (Figure 3). Collectively, many studies have reported that ACE2 plays important roles in SARS-CoV-induced ARDS.
Figure 3The role of ACE2/CCL2 signaling in lung fibrosis in SARS.
ACE2 overexpression can protect the lung from acute injury caused by viral and bacterial infections. Zou et al. demonstrated that H5N1 flu infection-induced lung injury could be alleviated by administrating recombinant hACE2 protein (
Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-kappa B signaling pathways.
) found that the affinity of the SARS-CoV-2 spike protein for binding to ACE2 was almost 20 times higher than that of the SARS-CoV spike protein, explaining why SARS-CoV-2 has a higher infection rate than SARS-CoV. A study by
) revealed that SARS-CoV-2 replication could be detected in the lungs of mice with hACE2 that had been infected with SARS-CoV-2. These mice presented the typical histopathology of interstitial pneumonia, with infiltration of high levels of macrophages and lymphocytes into the alveolar interstitium. In addition, SARS-CoV-2 antigens could be detected in bronchial epithelial cells, macrophages, and alveolar epithelia. However, the above phenomenon was not found in wild-type mice with SARS-CoV-2 infection, suggesting that ACE2 is the key factor mediating SARS-CoV-2-induced lung damage.
Since ACE2 is the target receptor for both SARS-CoV-2 and SARS-CoV, we hypothesize that the pathogenic mechanism of the two viruses might be very similar (
) investigated ACE2 expression in the lungs of a rodent model. These researchers found that the decrease in ACE2 was relatively slight between the young adult and the middle-aged groups, but the decrease was significant in older male rats compared with younger rats. This decrease in ACE2 with age may parallel the increase in COVID-19-related mortality in the older population.
As the host cell receptor for SARS-CoV-2, ACE2 exists as a dimer that includes the N-terminal peptidase domain (PD) and the C-terminal collectrin-like domain (CLD) (
). The PD of ACE2 recognizes the spike protein of SARS-CoV-2, and the CLD of ACE2 is cleaved by proteases such as transmembrane serine protease 2 (TMPRSS2), thus promoting SARS-CoV-2 spike protein-mediated entry into cells (
). Specifically, decreased expression of proteins such as ACE2 and TMPRSS2 in the airway epithelium in children may reduce viral entry, which might be the reason why SARS-CoV-2 leads to decreased lung injury in children compared with adults (
). A study by Bobeck et al. reported that Ang II, an inhibitor of the RAS system, was safely used in a COVID-19 patient with cardiomyopathy and vasodilatory shock, with a rapid improvement in her hemodynamics and vasopressor requirement without adverse effects (
Since the affinity of the spike protein of SARS-CoV-2 for ACE2 predominantly determines the symptoms of patients with COVID-19, ACE allele frequency might affect the morbidity, infection course, severity, and mortality of COVID-19 (
). A study by Guo etal. revealed that the ACE structure could be changed by altered amino acids in missense variants. The His378Arg (rs142984500) mutant is a weak enhancer and the Ser19Pro (rs73635825) mutant is a strong enhancer of SARS-CoV-2 S-protein binding. The His378Arg (rs142984500) mutant may not only reduce the activity of ACE2 peptidase but may also affect the process of SARS-CoV-2 S-protein and ACE2 binding. Additionally, the Ser19Pro (rs73635825) alteration may destabilize the helix of ACE2, affecting contact with the S-protein. Mutations such as Lys341Arg, Asp206Gly, Ile468Val, Arg219Cys/His, and Gly211Arg may significantly destabilize the local structure, and some of these mutations may have a minor effect on S-protein binding. The distribution of 12 characterized ACE2 missense variants in different populations was also identified by this study. Missense variants were present in East Asian (rs191860450), South Asian (rs751603885 and rs14877180), African (rs149039346, rs73635825, rs147311723, and rs138390800) and European (rs148771870) populations (
). These findings might help us to recognize individuals with an increased risk of COVID-19.
Inflammatory cytokines induced by SARS-CoV-2
The major cytokines induced by SARS-CoV-2 include IL-2, IL-4, IL-6, IL-7, IL-10, granulocyte colony stimulating factor (G-SCF), inducible protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP1A), tumour necrosis factor α (TNF-α), and interferon-γ (IFN-γ), which were observed at high levels in severe COVID-19 patients (
Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts.
Collectively, SARS-CoV-2 primarily enters type Ⅱ pneumocytes with ACE2 and replicates with the help of TMPRSS2. Next, the replicated SARS-CoV-2 induces a cytokine storm, contributing to hyperinflammation and alveolar edema, and ultimately leading to ARDS.
Could SARS-CoV-2-induced lung injury be attenuated by vitamin D?
Vitamin D3 is mainly produced in the skin after exposure to ultraviolet rays from sunlight (
). The active form of vitamin D, 1,25(OH)D (1,25 dihydroxy vitamin D), binds to the vitamin D receptor (VDR) to play anti-inflammatory and immune regulatory roles (
). VDR interacts with 1,25(OH)D and then binds to vitamin D responsive elements (VDREs) to inhibit or promote the expression of target genes, such as enhancement of ACE2 expression (
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system.
Vitamin D deficiency drives pulmonary inflammation in a human model of the acute respiratory distress syndrome induced by inhaled lipopolysaccharide in healthy volunteers.
) found a negative correlation between vitamin D level and the number of COVID-19 cases in some countries, including Iceland, Norway, Sweden, Finland, Denmark, the UK, Ireland, the Netherlands, Belgium, Germany, France, Switzerland, Italy, Spain, Estonia, Czech Republic, Slovakia, Hungary, Turkey, and Portugal. Furthermore, a negative correlation between vitamin D levels and the number of confirmed deaths caused by COVID-19 was also found in this study. There have been no actual data from the Chinese COVID-19 outbreak in relation to vitamin D levels until now. Vitamin D deficiency is common worldwide in all age groups due to decreased sun exposure and cutaneous synthesis, especially in northern regions. In particular, vitamin D deficiency is common among people during the winter and spring (particularly in the northern communities), especially in older and obese people (
). Therefore, vitamin D might attenuate SARS-CoV-2-induced lung injury.
Vitamin D and acute lung injury
Vitamin D and ACE2/RAS
ARDS and acute lung injury are associated with high fatality rates in patients affected by SARS-CoV-2 and SARS-CoV. ARDS and acute lung injury are associated with damaged pulmonary microvascular endothelial cells (PMVECs), which result in increased alveolar permeability and pulmonary edema (
). The balance between the expression of ACE1 and ACE2 is closely related to the ratio of Ang Ⅱ:Ang 1-7; an imbalance of Ang Ⅱ:Ang1-7 can lead to acute lung injury (
Interaction of N-acetyl-seryl-aspartyl-lysyl-proline with the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas axis attenuates pulmonary fibrosis in silicotic rats.
Role of Wnt4/beta-catenin, Ang II/TGF beta, ACE2, NF-kappa B, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone.
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system.
). The renoprotection of vitamin D is likely mediated by inhibiting the RAS, Ang Ⅱ, and NF-kB, with a subsequent reduction in proinflammatory cytokines, such as IL-18 and TGF-β (
Role of Wnt4/beta-catenin, Ang II/TGF beta, ACE2, NF-kappa B, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone.
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system.
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system.
). Pretreatment with calcitriol, a vitamin D agonist, significantly alleviated LPS-induced acute lung injury by upregulating ACE2 and downregulating ACE1, Ang Ⅱ, and AT1aR in an animal model (
Figure 4Vitamin D protects against acute lung injury. Green: increased expression or promotion by vitamin D. Red: decreased expression or inhibition by vitamin D. VDR = vitamin D receptor, VDREs = vitamin D responsive elements. Binding to the VDREs induces and represses the transcription of many genes.
Vitamin D Decreases respiratory syncytial virus induction of NF-kappa B-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state.
). IL-8, an endogenous chemotactic factor for neutrophils, is overexpressed in acute lung injury. Furthermore, 1,25(OH)2D3 can inhibit neutrophil infiltration and alleviate acute lung injury by downregulating IL-8 (
Vitamin D can induce the expression of antimicrobial peptides, which also have antiviral activity. Vitamin D has been reported to bind to VDR and then increase the human cathelicidin peptide LL37 and human β‐defensins (HBDs) in macrophages (
Collectively, vitamin D and SARS-CoV-2 can affect the same target, ACE2. Vitamin D might alleviate acute lung injury and ARDS induced by SARS-CoV-2 by regulating the RAS/ACE2 pathway, inflammatory cytokines, and antimicrobial peptides (Future 5).
Role of vitamin D supplementation in COVID-19 patients
Vitamin D supplementation might serve as a treatment to improve clinical outcomes in COVID-19 patients. A previous report showed that 1,25(OH)D is inversely correlated with the risk of ARDS, heart failure, and diabetes mellitus (
) reported four vitamin d-deficient COVID-19 patients who received treatment with vitamin D supplementation. The clinical outcomes included increased vitamin D levels, shorter lengths of hospital stay, lower oxygen requirements, and reduced inflammatory markers. A questionnaire-based study in Italy reported that vitamin D supplementation reduced the prevalence of COVID-19 infection (odds ratio 0.56; 95% confidence interval 0.32–0.99; p = 0.048) (
Since ACE2 is the host cell receptor for both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2. We speculate that vitamin D might alleviate lung injury induced by SARS-CoV-2 by upregulating ACE2, decreasing inflammatory cytokines, and increasing antimicrobial peptides. The efficacy of vitamin D in treatment of SARS-CoV-2 needs to be verified through more evidence-based medicine. In the future, we hope that randomized controlled clinical trials can be carried out to achieve this.
Ethical approval and consent to participate
Not applicable; review.
Consent for publication
Not applicable; review.
Clinical trial registration number and date if applicable
Not applicable; review.
Availability of data and material
No additional data are available.
Conflict of interest
The authors declare that they have no competing financial interests.
Funding sources
This work was supported by the National Science Foundation of China (81971433, 81971428, 82001593, 82071353) and a grant from the Clinical Discipline Program (Neonatology) from the Ministry of Health of China (1311200003303).
Author information
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China.
Role of Wnt4/beta-catenin, Ang II/TGF beta, ACE2, NF-kappa B, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone.
The next big threat to global health? 2019 novel coronavirus (2019-nCoV): What advice can we give to travellers?—Interim recommendations January 2020, from the Latin-American society for Travel Medicine (SLAMVI).
Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system.
Vitamin D deficiency drives pulmonary inflammation in a human model of the acute respiratory distress syndrome induced by inhaled lipopolysaccharide in healthy volunteers.
Interaction of N-acetyl-seryl-aspartyl-lysyl-proline with the angiotensin-converting enzyme 2-angiotensin-(1-7)-Mas axis attenuates pulmonary fibrosis in silicotic rats.
Vitamin D Decreases respiratory syncytial virus induction of NF-kappa B-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state.
Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-kappa B signaling pathways.
Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts.
Severe acute respiratory syndrome coronavirus fails to activate cytokine-mediated innate immune responses in cultured human monocyte-derived dendritic cells.
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