Source: Latest COVID-19 Research  Nov 22, 2020  2 years ago
Latest Research Shows That SARS-Cov-2 Suppresses ACE2 Activity In COVID-19 Patients While Inducing Expression Of The Interferon-Stimulated Genes (ISGS)
Latest Research Shows That SARS-Cov-2 Suppresses ACE2 Activity In COVID-19 Patients While Inducing Expression Of The Interferon-Stimulated Genes (ISGS)
Source: Latest COVID-19 Research  Nov 22, 2020  2 years ago
Latest COVID-19 Research: Spanish researchers from the Universitat Autònoma de Barcelona, Hospital del Mar Medical Research Institute (IMIM), the  Fight AIDS and Infectious Diseases Foundation-Spain, Hospital Universitari Germans Trias i Pujol, Badalona-Spain  and the Universtiat Central de Catalunya-Spain have in a new study revealed that SARS-CoV-2, the causative pathogen COVID-19, suppresses the expression and function of human angiotensin-converting enzyme 2 (ACE2) and induces the expression of interferon-stimulated genes (ISGs) at the initial phase of infection.

According to the study team there is an urgent need to elucidate the molecular mechanisms underlying the transmissibility and pathogenesis of SARS-CoV-2. ACE2 is a host ectopeptidase with well-described anti-inflammatory and tissue protective functions and the receptor for the SARS-CoV-2 coranavirus.
Detailed understanding of SARS-CoV-2-ACE2 interaction and the expression of antiviral host genes in early infection phase is crucial for fighting the pandemic.
The study team tested the significance of soluble ACE2 enzymatic activity longitudinally in positive nasopharyngeal swabs at two time points after symptom consultation, along with gene expression profiles of ACE2, its proteases, ADAM17 and TMPRRS2, and interferon-stimulated genes (ISGs), DDX58, CXCL10 and IL-6. Soluble ACE2 activity decreased during infection course, in parallel to ACE2 gene expression.
On the contrary, SARS-CoV-2 infection induced expression of the ISG genes in positive SARS-CoV-2 samples at baseline compared to negative control subjects, although this increase wanes with time. These changes positively correlated with viral load.
The study findings show the existence of mechanisms by which SARS-CoV-2 suppresses ACE2 expression and function casting doubt on the IFN-induced upregulation of the receptor. Moreover, the team shows that initial intracellular viral sensing and subsequent ISG induction is also rapidly downregulated.
The study findings offer new insights into ACE2 dynamics and inflammatory response in the human upper respiratory tract that may contribute to understand the early antiviral host response to SARS-CoV-2 infection.
The research findings are published on a preprint server and are currently being peer reviewed.
It is known that the entry of SARS-CoV-2 into host cells occurs via ACE2, which is an ectopeptidase and a functional receptor for the spike protein of many human coronaviruses. Since the emergence of the COVID-19 pandemic, many studies have investigated the cellular consequences of spike-ACE2 interaction. Some of these studies have shown that an interferon (IFN)-mediated induction of ACE2 expression occurs upon SARS-CoV-2 infection.
However regarding the mode of action of ACE2, it is known that the ectodomain of ACE2 is cleaved and released from the cell membrane by two proteases, namely ADAM17 and TMPRRS2. Moreover, TMPRRS2 facilitates the entry of SARS-CoV-2 into host cells by priming the spike protein. In the case of SARS-CoV-2 infection, the ectodomain of ACE2, which preserves its catalytic activity even after release from the cell membrane, may act as a soluble decoy to inhibit new viral infections, or may reduce local inflammation through its tissue-protective functions.
In order to better understand the molecular mechanism of SARS-CoV-2 transmission and pathogenesis, it is important to evaluate the cascade of inflammatory and immune signaling events that occur soon after the induction of SARS-CoV-2 infection.
The study team used nasopharyngeal samples collected from SARS-CoV-2-infected individuals to study the influence of ACE2 on host immune responses. Specifically, they investigated the direct impact of SARS-CoV-2 infection on ACE2 expression and function.
In the study, the nasopharyngeal swabs were collected from 40 non-hospitalized COVID-19 patients at 2 points in time: at the time of recruitment (day 0) and 3 days after. As a control, nasopharyngeal samples were also collected from 20 non-infected individuals. A quantitative reverse transcriptase-polymerase chain reaction was used to quantify the viral load, and a fluorescent enzymatic assay was used to analyze the ACE2 activity.
The researchers measured the enzymatic activity of soluble ACE2 in nasopharyngeal samples to mimic the ACE2 activity in the upper respiratory tract. They also checked the ACE2 activity in serum samples.
The study findings revealed that ACE2 activity was significantly lower in nasopharyngeal samples compared to that in serum samples. This indicates potential involvement of ACE2 in the upper respiratory tract.
Interestingly another observation was that compared to samples collected at day 0, samples collected on day 3 showed significantly lower ACE2 activity.
Also a significantly lower level of ACE2 expression was observed in SARS-CoV-2 positive swab samples. A further reduction in ACE2 expression was observed in day 3 samples. These findings indicate that SARS-CoV-2 is capable of downregulating both the expression and function of ACE2, probably by triggering the cleavage and release of ACE2 from the cell membrane.
Importantly another strong indication of the direct impact of SARS-CoV-2 infection on ACE2 function came from the observation that reduction in ACE2 expression and function was positively correlated with a drop in viral load over time (from day 0 to day 3).
In order to investigate the mode of action of SARS-CoV-2, the scientists measured the expressions of two main proteases (ADAM17 and TMPRRS2) that catalyze the cleavage of ACE2 ectodomain. The team observed a reduction in TMPRRS2 expression in infected samples compared to that in uninfected samples.
Importantly while checking the expression on IFN-stimulated genes, the team observed significantly higher expressions of DDX58, CXCL10 and IL-6 in SARS-CoV-2-infected samples collected at day 0. However, reduced expressions of these genes were noticed in infected samples collected at day 3. The initial induction of IFN-stimulated gene expression was positively correlated with higher viral load. Taken together, these findings indicate that soon after viral entry, an induction in IFN-mediated antiviral response occurs, which is subsequently suppressed by viral proteins to facilitate survival and infectivity.
The study findings contradict previous research showing induction of ACE2 expression by IFN upon SARS-CoV-2 infection. Moreover, the study reveals that viral load is associated with the initial induction of antiviral response and that upregulation of IFN-stimulated genes rapidly wanes within a few days of infection induction.
Numerous studies have shown that the presence of circulating ACE2 at the site of infection may be beneficial in terms of counterbalancing proinflammatory responses. A new role of soluble ACE2 as a blocker of SARS-CoV-2 has recently been identified. Based on the current study findings, the scientists suggest that recombinant ACE2 can be applied locally at the initial phase of infection to control the viral spread.
A recent study reports the discovery of a truncated form of ACE2 gene (dACE2) as the IFN-inducible isoform of ACE2 not acting as viral receptor nor as carboxipeptidase.
This new finding would be in line with this study  results showing no significant changes in ACE2 soluble activity upon SARS-CoV-2 infection, concomitant to a decrease in ACE2 gene expression. In contrast, a clear induction of IFN stimulated genes is observed upon SARS-CoV-2 infection, also supporting the idea that full length ACE2 is not an ISG and that viral infection is indeed downregulating its expression.
Importantly, ACE2 expression and function correlated with viral load, further stressing the key role of ACE2 in SARS-CoV-2 pathogenesis.
Collectively, the study findings support the existence of IFN-independent mechanisms by which SARS-CoV-2 suppress ACE2 expression and function.
SARS-CoV-2 induction of ISGs at the site of infection is temporary, suggesting that the virus may also suppress intracellular viral sensing and subsequent ISG induction for favoring viral replication, although its relative contribution to disease outcome cannot be solved due to the characteristics of the studied cohort, all presenting mild forms of the disease. In depth evaluation of early changes in innate immune activation at the site of infection in patients with distinct disease severity may shed light on its putative effects on viral associated pathogenesis that may lead to different infection outcomes.
Deciphering the regulation of the ACE2 and ISG expression and function in SARS-CoV-2 target cells is a step forward in linking ACE2 levels with viral damage and COVID-19 pathology that may help to design better strategies to efficiently clear the SARS-CoV-2 virus and minimize tissue damage. On the other hand, understanding the innate immune responses to SARS-CoV-2 and its immunoevasion approaches will improve our understanding of pathogenesis, virus clearance, and contribute toward vaccine and immunotherapeutic design and evaluation
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