Abstract:The current pandemic of novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) poses a significant global public health threat. While urgent regulatory measures in control of the rapid spread of this virus are essential, scientists around the world have quickly engaged in this battle by studying the molecular mechanisms and searching for effective therapeutic strategies against this deadly disease. At present, the exact mechanisms of programmed cell death upon SARS-CoV-2 infection remain to be elucid… Show more
“…The reduction of the protein level of several proteins such as p65 at 72 h might be due to SARS-CoV-2-triggered cell death. 1 , 25 – 27 Consistent with the previous studies, 2 , 3 , 18 , 20 , 21 our results revealed that SARS-CoV-2 infection could lead to the activation of host inflammatory responses, including NF-κB signaling. Fig.…”
The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid–liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.
“…The reduction of the protein level of several proteins such as p65 at 72 h might be due to SARS-CoV-2-triggered cell death. 1 , 25 – 27 Consistent with the previous studies, 2 , 3 , 18 , 20 , 21 our results revealed that SARS-CoV-2 infection could lead to the activation of host inflammatory responses, including NF-κB signaling. Fig.…”
The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid–liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation. Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.
“…Furthermore, Fas-mediated apoptosis of virus-infected cells is a major mechanism of resolution of viral infections 43 . Delayed apoptosis is reported to be one of the strategies exploited by SARS-CoV-2 in the early stages of infection to facilitate viral replication 43,44 . Additional insights for the role of sFas in COVID-19 can be gleaned from results of recent drug trials.…”
The virus SARS-CoV-2 can exploit biological vulnerabilities in susceptible hosts that predispose to development of severe COVID-19. Previous reports have identified several host proteins related to the interferon response (e.g. OAS1), interleukin-6 signalling (IL-6R), and the coagulation cascade (linked via ABO) that were associated with risk of COVID-19. In the present study, we performed proteome-wide genetic colocalisation tests leveraging publicly available protein and COVID-19 datasets, to identify additional proteins that may contribute to COVID-19 risk. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble FAS (colocalisation probability > 0.9, p = 1 x 10-4), implicating FAS-mediated apoptosis as a potential target for COVID-19 risk. We also undertook polygenic (pan) and cis-Mendelian randomisation analyses that showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal was associated with plasma concentrations of several proteins, with the strongest association observed with CD209 in several proteomic datasets. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.
“…Host cell apoptosis, a protective mechanism in cells infected with viruses, plays a critical role in normal physiological processes and virus pathogenesis [69]. Although apoptotic defense is one mechanism to curtail virus spread, SARS-CoV -2 has been shown to employ sophisticated molecular strategies such as miRNAs to subvert and neutralize host cell apoptosis [70]. For instance, two virus-encoded miRNAs, MD2-5p and MR147-3p, have been hypothesized to repress the expression of pro-apoptotic elements and cation transport regulator-like protein 1 (CHAC1) and RAD9A genes, respectively [26].…”
To date, proposed therapies and antiviral drugs have been failed to cure coronavirus disease 2019 (COVID-19) patients. However, at least two drug companies have applied for emergency use authorization with the United States Food and Drug Administration for their coronavirus vaccine candidates and several other vaccines are in various stages of development to determine safety and efficacy. Recently, some studies have shown the role of different human and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microRNAs (miRNAs) in the pathophysiology of COVID-19. miRNAs are non-coding single-stranded RNAs, which are involved in several physiological and pathological conditions, such as cell proliferation, differentiation, and metabolism. They act as negative regulators of protein synthesis through binding to the 3′ untranslated region (3′ UTR) of the complementary target mRNA, leading to mRNA degradation or inhibition. The databases of Google Scholar, Scopus, PubMed, and Web of Science were searched for literature regarding the importance of miRNAs in the SARS-CoV-2 life cycle, pathogenesis, and genomic mutations. Furthermore, promising miRNAs as a biomarker or antiviral agent in COVID-19 therapy are reviewed.
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