ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19

Pinto, Bruna G G; Oliveira, Antônio Edson Rocha; Singh, Youvika; Jimenez, Leandro; Gonçalves, André Nicolau Aquime; Ogava, Rodrigo L T; Creighton, Rachel; Peron, Jean Pierre Schatzmann; Nakaya, Hidehiko

doi:10.1093/infdis/jiaa332

Cited by 317 publications

(309 citation statements)

References 45 publications

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“…Emerging evidence indicates high-risk individuals with SARS-CoV-2 have high rates of alveolar epithelial type 2 (AT2) cell infection, suggesting disease severity may be related to higher alveolar expression of the SARS-CoV-2 receptor angiotensin converting enzyme (ACE2) and its co-receptor transmembrane protease/serine subfamily member 2 (TMPRSS2) 8,9 . In fact, a recent meta-analysis of 700 people with predicted COVID-19 co-morbidities found that their lungs expressed high levels Ace2 mRNA 10 . ACE2 is a zinc containing metalloprotease present at the surface of cells in the lung, heart, intestines, kidneys, and brain.…”

Section: Introductionmentioning

confidence: 99%

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

Yee

Cohen

Haak

et al. 2020

Preprint

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The severity of COVID-19 lung disease is higher in the elderly and people with pre-existing co-morbidities. People who were born preterm may be at greater risk for COVID-19 because their early exposure to oxygen at birth increases their risk of being hospitalized when infected with RSV and other respiratory viruses. Our prior studies in mice showed how high levels of oxygen (hyperoxia) between postnatal days 0-4 increases the severity of influenza A virus infections by reducing the number of alveolar epithelial type 2 (AT2) cells. Because AT2 cells express the SARS-CoV-2 receptors angiotensin converting enzyme (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2), we expected their expression would decline as AT2 cells were depleted by hyperoxia. Instead, we made the surprising discovery that expression of Ace2 and Tmprss2 mRNA increases as mice age and is accelerated by exposing mice to neonatal hyperoxia. ACE2 is primarily expressed at birth by airway Club cells and becomes detectable in AT2 cells by one year of life. Neonatal hyperoxia increases ACE2 expression in Club cells and makes it detectable in 2-month-old AT2 cells. This early and increased expression of SARS-CoV-2 receptors was not seen in adult mice who had been administered the mitochondrial superoxide scavenger mitoTEMPO during hyperoxia. Our finding that early life insults such as hyperoxia enhances the age-dependent expression of SARS-CoV-2 receptors in the respiratory epithelium helps explain why COVID-19 lung disease is greater in the elderly and people with pre-existing co-morbidities.

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Section: Introductionmentioning

confidence: 99%

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

Yee

Cohen

Haak

et al. 2020

Preprint

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“…Intriguingly, ACE2 mRNA levels also appear to be regulated by a multitude of factors, including age (11), tobacco smoke (12), and other respiratory tract infections (e.g., rhinovirus and influenza virus) (9) potentially via the canonically antiviral type I and II interferon (IFN) pathways (9,12,13). Thus, a tempting hypothesis that remains to be experimentally validated is that external or biological factors leading to enhanced ACE2 expression may exacerbate SARS-CoV-2 replication and/or expand its cellular tropism (14), thereby increasing the severity of COVID-19 in individuals of certain risk groups, including the elderly, smokers, and those with coinfections or comorbidities (15).…”

mentioning

confidence: 99%

Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2

Busnadiego

Fernbach

Pohl

et al. 2020

mBio

155

164

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is a recently emerged respiratory coronavirus that has infected >23 million people worldwide with >800,000 deaths. Few COVID-19 therapeutics are available, and the basis for severe infections is poorly understood. Here, we investigated properties of type I (β), II (γ), and III (λ1) interferons (IFNs), potent immune cytokines that are normally produced during infection and that upregulate IFN-stimulated gene (ISG) effectors to limit virus replication. IFNs are already in clinical trials to treat COVID-19. However, recent studies highlight the potential for IFNs to enhance expression of host angiotensin-converting enzyme 2 (ACE2), suggesting that IFN therapy or natural coinfections could exacerbate COVID-19 by upregulating this critical virus entry receptor. Using a cell line model, we found that beta interferon (IFN-β) strongly upregulated expression of canonical antiviral ISGs, as well as ACE2 at the mRNA and cell surface protein levels. Strikingly, IFN-λ1 upregulated antiviral ISGs, but ACE2 mRNA was only marginally elevated and did not lead to detectably increased ACE2 protein at the cell surface. IFN-γ induced the weakest ISG response but clearly enhanced surface expression of ACE2. Importantly, all IFN types inhibited SARS-CoV-2 replication in a dose-dependent manner, and IFN-β and IFN-λ1 exhibited potent antiviral activity in primary human bronchial epithelial cells. Our data imply that type-specific mechanisms or kinetics shape IFN-enhanced ACE2 transcript and cell surface levels but that the antiviral action of IFNs against SARS-CoV-2 counterbalances any proviral effects of ACE2 induction. These insights should aid in evaluating the benefits of specific IFNs, particularly IFN-λ, as repurposed therapeutics. IMPORTANCE Repurposing existing, clinically approved, antiviral drugs as COVID-19 therapeutics is a rapid way to help combat the SARS-CoV-2 pandemic. Interferons (IFNs) usually form part of the body’s natural innate immune defenses against viruses, and they have been used with partial success to treat previous new viral threats, such as HIV, hepatitis C virus, and Ebola virus. Nevertheless, IFNs can have undesirable side effects, and recent reports indicate that IFNs upregulate the expression of host ACE2 (a critical entry receptor for SARS-CoV-2), raising the possibility that IFN treatments could exacerbate COVID-19. Here, we studied the antiviral- and ACE2-inducing properties of different IFN types in both a human lung cell line model and primary human bronchial epithelial cells. We observed differences between IFNs with respect to their induction of antiviral genes and abilities to enhance the cell surface expression of ACE2. Nevertheless, all the IFNs limited SARS-CoV-2 replication, suggesting that their antiviral actions can counterbalance increased ACE2.

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“…Chromatin immunoprecipitation sequencing (ChIP-seq) showed that EZH2 depletion induced H3K27me3 decrease, with concomitant H3K27ac increase, at ACE2 promoter in human ESCs (Li Y. et al, 2020). The role of H3 methylation and acetylation in the epigenetic regulation of ACE2 was also hypothesized by Pinto et al, who demonstrated that co-morbidities such as hypertension, diabetes, and chronic obstructive lung disease increase ACE2 transcription in the lung (Pinto et al, 2020).…”

Section: Transcriptional Post-transcriptional and Post-translationamentioning

confidence: 87%

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

Saponaro

Rutigliano

Sestito

et al. 2020

Front. Mol. Biosci.

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Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

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ACE2 Expression Is Increased in the Lungs of Patients With Comorbidities Associated With Severe COVID-19

Cited by 317 publications

References 45 publications

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

Neonatal hyperoxia enhances age-dependent expression of SARS-CoV-2 receptors in mice

Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

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