6147 virus

In the literature, there are reports supporting [ 31 — 33 ] and refuting [ 34 — 36 ] this hypothesis. Since the beginning of the COVID pandemic, hypertension and diabetes have been correlated with higher risk of mortality, and initial reports speculated that angiotensin converting enzyme inhibitors ACEi and angiotensin receptor blockers ARBs , which are commonly used therapeutic agents for these conditions, would up-regulate ACE2 expression, thus increasing the risk of severe illness [ 37 ].

Recent evidence has challenged this hypothesis, demonstrating both mechanistically and in large cohort studies that ACEi and ARBs do not up-regulate ACE2 and are not associated with an increased mortality [ 35 , 36 ]. Interestingly, asthma has not been reported as a risk factor for COVID illness and disease progression.

Kimura and colleagues showed that interleukin IL , a cytokine up-regulated in type 2 asthma, down-regulates the level of ACE2 [ 38 ]. Furthermore, Jackson and colleagues demonstrated a negative correlation between ACE2 expression and allergen sensitization and asthma [ 39 ]. Intriguingly, Peters and colleagues found that asthmatic subjects treated with inhaled corticosteroids ICS had low ACE2 expression compared with untreated subjects, a finding suggesting that ICS treatment could be a predictor of decreased susceptibility to SARS-CoV-2 infection [ 40 ].

ACE2 is normally localized on the plasma membrane mACE2 with the N-terminal containing the catalytic site protruding on the extracellular space using as substrate different active peptides present in the interstitium.

Interestingly, TACE inhibitors can decrease viral entry in vitro and in vivo demonstrating their key role in determining SARS-CoV infectivity and their potential use as a target for antiviral therapies [ 43 ].

The significance of ACE2 shedding has not been fully elucidated, but in the context of the COVID pandemic, the comprehension of the mechanism leading to ACE2 shedding, sACE2 function, and its plasma level can lead to the development of better therapies and diagnostic tools to follow disease progression and severity. It cleaves ACE2 at the intracellular C-terminal domain and, differently from ADAM17 [ 45 ], does not produce a soluble form that retains the catalytic function [ 41 ].

Different studies have demonstrated that an increased level of sACE2 correlates with disease severity [ 48 , 49 ], possibly due to an increase in AngII. The overactivation of BRB1 receptor has been shown to promote inflammation and coagulation.

The evidence that ACE2 can be cleaved from multiple proteases upon different stimuli indicates that the post-translational regulation of this ectoenzyme is of great importance in managing tissue homeostasis. Due to the main role of ACE2 in mediating SARS-CoV-2 entry into cells, many studies have speculated whether ACE2 expression and polymorphism and serum sACE2 levels could explain why some people are more prone to experience a severe phenotype while others remain asymptomatic.

Studies that aimed to find mutations in the ACE2 sequences and allele frequency in different populations have demonstrated the existence of specific variance that could affect SARS-CoV-2 binding [ 52 — 54 ]. Indeed, since the beginning of this pandemic, opposite assumptions have been made. Some researchers think that elevated levels of sACE2 may be protective because they are capable of inhibiting the binding of SARS-CoV-2 to membrane-bound ACE2 [ 4 ] and would explain why women and children are less susceptible [ 57 ].

Dissecting the roles that ACE2 has in maintaining organismal physiology will help us to better comprehend why its dysregulation caused by SARS-CoV-2 can have such a devastating effect, especially in the elderly with comorbidities. In the next sections, we will describe the molecular pathways in which ACE2 plays an important role. We will focus on the role that ACE2 plays in counterbalancing the RAAS but also on its important function in the kinin-kallikrein system KKS that has been mostly neglected although it plays an essential part in regulating the inflammatory process.

Despite having a high degree of homology with ACE, ACE2 shows a remarkable difference in substrate selection, catalyzing with high efficiency the conversion of the vasoconstrictor AngII in Ang that binds and activates its own seven-transmembrane G protein-coupled receptor GPCR called MAS to exert anti-inflammatory and anti-remodeling effects or, with less efficiency, the formation of Ang from AngI, which can be converted to Ang by ACE [ 60 ].

In doing so, ACE2 plays a counterbalance action in the RAAS, which is a critical regulator of blood volume and systemic vascular resistance and contributes to sodium reabsorption, inflammation, and fibrosis, preventing the possible adverse effect of AngII accumulation.

There is evidence that AT1R can induce apoptosis in lung alveolar epithelial cells in response to AngII in rat and human alveolar epithelial cells [ 63 ]. Furthermore, AngII promotes endothelial dysfunction through cyclooxygenase-2 COX-2 activation, which generates vasoactive prostaglandins and reactive oxygen species ROS [ 64 ].

Therefore, the activation of the immune response caused by the infection in combination with the high level of AngII could result in the hyperinflammatory state that is seen in the late phase of SARS-CoVinfected patients. In fact, the produced peptide alamandine is able to bind to the MAS-related GPCR member D MrgD and exerts a protective action promoting vasorelaxation and an antiproliferative effect [ 68 ]. The KKS plays a key role in the regulation of several physiological processes such as coagulation, inflammation, and pain [ 69 ].

Moreover, BK positively regulates tissue plasminogen secretion tPA and, therefore, plays an important role in thrombus formation [ 72 ]. Evidence has demonstrated that activation of BRB1 is able to aggravate the inflammation by causing the further release of proinflammatory cytokines and promoting neutrophil infiltration [ 75 ]. Nonetheless, an approach that could target both pathways to fight against COVID has already been suggested [ 79 ]. Administration of hrACE2 is well tolerated in healthy subjects [ 81 ], and it has been successfully used to treat patients with ARDS [ 82 ].

APN01 is a rhACE2 that is fully glycosylated 7 glycosylation sites and occurs as a stable noncovalent homodimer. The use of twice-daily doses of APN01 infusion resulted in a rapid decrease in plasma AngII levels and an increase in Ang and Ang levels, as well as a trend to a decrease in plasma IL-6 concentrations [ 82 ]. Furthermore, a more effective way for the delivery of shrACE2 that would decrease protease degradation has already been suggested [ 84 ].

Another strategy that is being investigated in clinical trials is the administration of an antibody or a single-chain antibody fragment scFv that binds ACE2 and blocks the interaction of spike protein on the virion to ACE2 [ 85 ]. The rapid rate of adaptive mutations combined with high transmissibility renders coronaviruses an ongoing threat of causing future pandemics, with especially high risk for the elderly [ 87 ].

Although the scientific world is making an extraordinary effort, we are still far from fully understanding whether the overactivation of the immune system and the state of hyperinflammation due to SARS-CoV-2 infection can be controlled [ 88 ]. This would be particularly important in people with comorbidities such as diabetes and hypertension, which are conditions already associated with an inflammatory state.

In conclusion, we believe that further efforts should be made to fully understand ACE2 transcriptional regulation and post-translational modification during the course of COVID and in response to treatments.

In fact, as already discussed, contrasting hypotheses have been formulated concerning the effect of therapies taken by millions of people that might increase ACE2 expression and susceptibility to SARS-CoV-2 infection. Furthermore, although COVID is still primarily described as a respiratory viral illness, it is increasingly evident that it is a multisystemic disease. Therefore, it is essential to acquire a greater knowledge of the role that ACE2 plays in different organs and physiological pathways because of its widespread tissue expression.

This, in turn, could have significant implications for identifying better therapies and screening tools to assess disease progression and severity. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Publisher's Note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology Information , U. Author information Article notes Copyright and License information Disclaimer. Mario Cazzola, Email: ti. Corresponding author. Received Sep 15; Accepted Nov 5. How to stay warm in the winter without breaking the bank.

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Before Thursday, the single-day high had been in January The recent rapid spread of coronavirus, attributed to the contagious omicron variant, has prompted long lines at public testing sites and some universities in the state to delay student returns for the spring semester, news outlets reported. The total is roughly double the number of those in the hospital a month ago. The state said more than 76, tests were completed on Thursday, not including at-home tests.

The rapid spread led Duke University to announce on Friday that spring semester classes will now remain remote until Jan. Elizabeth City State University and Methodist University in Fayetteville also have announced that the start of spring semester will be delayed until Jan.

UNC-Chapel Hill announced Friday that individual deans would make decisions on class flexibility within their schools.

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