Plasma ACE2 species are differentially altered in COVID‐19 patients

García‐Ayllón, María‐Salud; Moreno-Pérez, Óscar; García-Arriaza, Juan; Ramos‐Rincón, José Manuel; Cortés‐Gómez, María‐Ángeles; Brinkmalm, Gunnar; Andrés, Mariano; León-Ramírez, José-Manuel; Boix, Vicente; Gil, Joan; Zetterberg, Henrik; Estéban, Mariano; Merino, Esperanza; Sáez‐Valero, Javier

doi:10.1096/fj.202100051r

Cited by 17 publications

(29 citation statements)

References 76 publications

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“…However, longitudinal evaluation of soluble ACE2 in patient-matched samples showed a significant decrease, indicating that viral infection is significantly affecting ACE2 function. Indeed, soluble ACE2 measured in plasma showed a decrease over time, in line with previous reports [ 14 , 35 , 36 ]. Overall, we demonstrate that SARS-CoV-2 infection induces shedding of ACE2 from cell membranes, leading to increased levels of the soluble active form of ACE2 in situ; however, it is also found later on in plasma, when the infection has spread systemically.…”

Section: Discussionsupporting

confidence: 91%

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

Gutiérrez-Chamorro

Riveira-Muñoz

Barrios

et al. 2021

Viruses

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Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-COV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.

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Section: Discussionsupporting

confidence: 91%

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

Gutiérrez-Chamorro

Riveira-Muñoz

Barrios

et al. 2021

Viruses

View full text Add to dashboard Cite

show abstract

“…One explanation may be due to differences in neutralization between active ACE2 and degradation products (likely neutralization inactive) in patients, and that cannot be discriminated with our assays. In this regard, it has been described recently differences in ACE2 degradation in COVID patients ( 21 ). Soluble ACE2 is also present in human bronchoalveolar lavage fluid from healthy subjects ( 42 ) and may act as decoy avowing productive infection.…”

Section: Discussionmentioning

confidence: 91%

“…A possible caveat in our interpretation is that infected subjects may have suffered a degradation of ACE2 to lower levels than those before the infection due to the complex dynamics of the angiotensin system and degradation by the virus ( 3 ) see also ( 14 ) for a review. To minimize this possibility, all serum samples from seropositive people were taken at least 50 days after the disappearance of symptoms, a time likely enough for the RAS system, and especially serum ACE2, to reach homeostatic levels as before the infection, a time which is supported by a recent report ( 21 ). Moreover, we have analysed samples of unexposed healthy people.…”

Section: Discussionmentioning

confidence: 99%

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19

et al. 2022

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BackgroundCOVID‐19 can generate a broad spectrum of severity and symptoms. Many studies analysed the determinants of severity but not among some types of symptoms. More importantly, very few studies analysed patients highly exposed to the virus that nonetheless remain uninfected.MethodsWe analysed serum levels of ACE2, Angiotensin II and anti-Spike antibodies in 2 different cohorts at high risk of viral exposure, highly exposed but uninfected subjects, either high risk health care workers or persons cohabiting with infected close relatives and seropositive patients with symptoms. We tested the ability of the sera of these subjects to neutralize lentivirus pseudotyped with the Spike-protein.ResultsWe found that the serum levels of ACE2 are significantly higher in highly exposed but uninfected subjects. Moreover, sera from this seronegative persons can neutralize SARS-CoV-2 infection in cellular assays more strongly that sera from non-exposed negative controls eventhough they do not have anti-CoV-2 IgG antibodies suggesting that high levels of ACE2 in serum may somewhat protect against an active infection without generating a conventional antibody response. Finally, we show that among patients with symptoms, ACE2 levels were significantly higher in infected patients who developed cutaneous as compared with respiratory symptoms and ACE2 was also higher in those with milder symptoms.ConclusionsThese findings suggest that soluble ACE2 could be used as a potential biomarker to predict SARS-CoV-2 infection risk and to discriminate COVID-19 disease subtypes.

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“…2 F). The truncated form (approximately 75 kDa) of the ACE2 protein has also been detected in human plasma [ 21 ] and COS7 cells [ 22 ]. These results suggest that IFN-λ1 exerted weaker effects on the induction of proinflammatory cytokines and ACE2 than other IFNs.…”

Section: Resultsmentioning

confidence: 99%

The Priming Potential of Interferon Lambda-1 for Antiviral Defense in the Oral Mucosa

et al. 2022

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The oral mucosa is one of the first lines of the innate host defense system against microbial invasion. Interferon (IFN) lambda-1 (IFN-λ1), a type III IFN, exhibits type I IFN-like antiviral activity. In contrast to ubiquitously expressed type I IFN receptors, IFN-λ receptor 1 (IFN-λR1), which has higher affinity for type III IFNs than low-affinity interleukin (IL)-10 receptor 2, is mainly expressed on epithelial cells. Although IFN-λ1 has been shown to exert antiviral effects in the respiratory tract, gastrointestinal tract, and skin, the regulation of type III IFN receptor expression and its functions in the oral mucosa remain unclear. We herein showed the expression of IFN-λR1 in human gingival keratinocytes. The expression of IL-6, angiotensin-converting enzyme 2 (a critical molecule for severe acute respiratory syndrome coronavirus 2 infection), and IL-8 in human primary gingival keratinocytes (HGK) were significantly higher following treatments with either type I IFN (IFN-β) or type II IFN (IFN-γ) than with IFN-λ1. However, the IFN-λ1 treatment strongly induced toll-like receptor (TLR) 3 and retinoic acid-inducible gene I (RIG-I), which mainly recognize viral nucleic acids, via the STAT1-mediated pathway. Furthermore, a stimulation with a RIG-I or TLR3 agonist promoted the production of IL-6, IL-8, and IFN-λ in HGK, which was significantly enhanced by a pretreatment with IFN-λ1. These results suggest that IFN-λ1 may contribute to the activation of innate immune responses to oral viral infections by up-regulating the expression of RIG-I and TLR3 and priming their functions in keratinocytes. Supplementary Information The online version contains supplementary material available at 10.1007/s10753-022-01624-1.

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Plasma ACE2 species are differentially altered in COVID‐19 patients

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 17 publications

References 76 publications

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19

The Priming Potential of Interferon Lambda-1 for Antiviral Defense in the Oral Mucosa

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