COVID-19 Central Research Database

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  • Interaction of the Coronavirus Nucleoprotein with Nucleolar Antigens and the Host Cell

    The interaction of viral proteins with nucleolar antigens may account for why viral proteins have been observed in the nucleolus and may also explain the viral exploitation of nucleolar function, leading to alterations in host cell transcription, translation, and disruption of the host cell cycle to facilitate viral replication. In this study we wanted to investigate whether coronavirus N proteins interacted with two nucleolar antigens, fibrillarin and nucleolin. Interaction with either or both of these antigens might explain our previous observations that coronavirus N proteins localized to the nucleolus (26, 64). Because proteins that localize to the nucleolus have been implicated in cell growth and the cell cycle (11, 40, 41), we also wished to investigate whether coronavirus N proteins affect cell division. Our data indicated that rather than adopting its normal (globular) Christmas tree-like appearance (5), in infected cells fibrillarin was distributed throughout the nucleolus and was possibly more concentrated in the nucleolar periphery. Transfection of either HeLa or Vero cells with plasmids that expressed either the IBV (type III coronavirus) or MHV (type II coronavirus) N proteins also resulted in a change in distribution of fibrillarin, in a similar manner to that observed in virus-infected cells. However, unlike HIV Rev protein, which localizes to the nucleolus with a pattern similar to fibrillarin (16) (determined by confocal microscopy), the coronavirus N protein localized uniformly throughout the nucleolus (see, e.g., Fig. 3F) (26, 64). The redistribution of fibrillarin, as a consequence of virus infection, is not unique to coronaviruses. Infection of cells with adenovirus also resulted in the redistribution of fibrillarin (46). To our knowledge this is the first time this has been demonstrated for an RNA virus. The reason for reorganization of fibrillarin to the perinucleolar region is unknown; however, the perinucleolar compartment has been implicated to play a role in transcription and in RNA metabolism in the host cell (28). To investigate whether the coronavirus N protein also associates with fibrillarin in the cytoplasm, experiments with a GFP-fibrillarin fusion protein indicated that both fibrillarin and IBV or MHV N protein colocalized in the perinuclear region and nucleolus (e.g., Fig. 6C and 7C, respectively). The nucleolar functions of fibrillarin are well established and include a role in ribosome assembly (60) and, as a factor of the nucleolus, in cell cycle regulation (11). Experiments that blocked fibrillarin with antibody prevented the translocation of fibrillarin to the nucleoli and resulted in the reduction or inhibition of PolI transcription (19); by redistributing fibrillarin N protein might have a similar effect. Alternatively, by interacting with fibrillarin, N protein could potentially affect ribosomal biogenesis and, therefore, have a concomitant effect on host cell translation. During MHV infection, host cell translation is decreased, although translation of viral mRNAs is either unaffected or upregulated (24, 55). N protein may therefore interact with nucleolar components to improve translation of virus mRNAs, perhaps by sequestering ribosomes (or parts thereof) to viral mRNAs (26). Unfortunately, from the point of view of this study, the monoclonal antibody against nucleolin, used in immunofluorescence, only recognized human nucleolin (in accordance with the manufacturer’s guidelines [Leinco Technologies]), and this limited the study of possible redistribution of nucleolin by N protein to HeLa cells which expressed MHV N protein. While our data suggested that nucleolin was not reorganized in these cells, it is not possible to conclude that this does not occur in virus-infected cells or with other coronavirus N proteins expressed in species-specific cell types. For example, nucleolin is retained in the cytoplasm in poliovirus-infected cells (62), probably because cytoplasmic-nuclear trafficking is prevented (23), and adenovirus infection results in the redistribution of nucleolin to the cytoplasm (38). Binding studies with purified immobilized phosphorylated or nonphosphorylated IBV N protein and nuclear extracts prepared from Vero cells indicated that there was a direct interaction between N protein and nucleolin (Fig. 8E, lanes 1 and 3, respectively). Two recombinant His-tagged proteins were used to investigate the specificity of nucleolin binding to N protein, HIV core (p24) protein, and DcuR, a DNA-binding protein isolated from E. coli (22). Nucleolin did not bind to either of these immobilized proteins or to the NTA beads in the absence of protein, indicating that nucleolin specifically interacted with N protein. Interestingly, the data indicated that immobilized Nphos protein bound more nucleolin than Nnonphos protein, a finding that is contrary to what would be predicted if the protein associated by electrostatic charge alone. Reference & Source information: Read more on :

  • Contribution of monocytes and macrophages to the local tissue inflammation & cytokine storm in COVID-19.

    The COVID -19 -, SARS - and MERS -related coronaviruses share many genomic and structural similarities. However, the SARS -CoV -2 is less pathogenic than SARS -CoV and MERS -CoV. Despite some differences in the cytokine patterns, it seems that the cytokine storm plays a crucial role in the pathogenesis of COVID - 19 -, SARS - and MERS. Monocytes and macrophages may be infected by SARS - CoV -2 through ACE2 -dependent and ACE2 -independent pathways. SARS -CoV -2 can effectively suppress the anti -viral IFN response in monocytes and macrophages. Since macrophages and dendritic cells (DCs ) act as antigen presenting cells (APCs ), the infection of these cells by SARS -CoV -2 impair s the adaptive immune responses against the virus. Upon infection, monocytes migrate to the tissue s where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. The SARS -CoV - 2 -infected monocytes and macrophages can produce large amounts of numerous types of pro - inflammatory cytokines and chemokines, which contribute to local tissue inflammation and a dangerous systemic inflammatory response called cytokine storm. Both local tissue inflammation and the cytokine storm play a fundamental role in the development COVID -19 -related complications, such as acute respiratory distress syndrome (ARDS), which is a main cause of death in COVID - 19 patients. Here, we describe the monocytes and macrophage responses during Journal Pre-proof Journal Pre-proof - 3 - Jafarzadeh A. et al. severe coronavirus infections, while highlighting potential therapeutic interventions to attenuate macrophage -related inflammatory reactions in possible approaches for COVID -19 treatment. In mucosal respiratory infections, alveolar macrophages serve as the first anti -viral defense through production type I IFNs. Monocytes/macrophages are the principal leukocytes attracted to the alveolar space in the initial response to respiratory viral infection. Monocytes and macrophages may be directly infected by SARS -CoV -2 through ACE2 -dependent process or indirectly infected via ACE2 -independent pathways using L -SIGN, DC -SIGN, CD147, ADE, and phagocytosis of virus - containing apoptotic bodies. SARS -CoV -2 can effectively suppress the anti -viral IFN response in monocytes and macrophages. As DCs, monocytes, and macrophages can act as APCs, the SARS -CoV -2 infection of these cells impairs the anti -viral adaptive immune responses. Upon infection, monocytes migrate to tissues where they become infected resident macrophages, allowing viruses to spread through all organs and tissues. Both infected - and uninfected macrophages can be found in the lungs of patients with COVID -19. Monocytes and macrophages can communicate with other cell types via direct cell -cell contacts, leading to the virus dissemination. The SARS -CoV - 2 -infected monocytes and macrophages can produce large amounts of numerous types of pro -inflammatory cytokines and chemokines , which contribute to the local tissue inflammation and Journal Pre-proof Journal Pre-proof - 32 - Jafarzadeh A. et al. dangerous systemic inflammatory response as named cytokine storm. Low expression of ACE2 by monocytes/macrophages of COVID -19 patients may also promote pathological reactions due to pro -inflammatory properties of angiotensin II and dysfunction of the renin -angiotensin system (RAS). Both local tissue inflammation and cytokine storm play a fundamental role in the development of COVID -19 -related complications, such ARDS, which is the main cause of death in SARS -CoV - 2 -infected patients (Figure 3B) . Although the modulation of macrophage activation may be considered as a promising therapeutic approach for COVID -19, a better understanding of macrophage polarization and heterogeneity during COVID -19 is required. Moreover, the patterns of the macrophage polarization may vary during the different stages of the COVID -19 and need to be clarified in future researches. Various types of macrophages can perform a decisive role in the outcome of the COVID -19. Since macrophage polarization is a reversible process, it is necessary to clarify the factors affecting macrophage plasticity during COVID -19 and how to manipulate macrophage plasticity in a favourable direction. Moreover, macrophages from different organs may express different markers. The better understanding of which subsets of monocytes/macrophages drive disease pathology is important for the development of proper therapeutic interventions [103]. Reference & Source information: Read More on :

  • Potential effects of curcumin in the treatment of COVID-19 infection

    The main clinical manifestation of COVID-19 is the presence of respiratory symptoms, but some patients develop severe cardiovascular and renal complications. There is an urgency to understand the mechanism by which this virus causes complications so as to develop treatment options. Curcumin, a natural polyphenolic compound, could be a potential treatment option for patients with coronavirus disease. In this study, we review some of the potential effects of curcumin such as inhibiting the entry of virus to the cell, inhibiting encapsulation of the virus and viral protease, as well as modulating various cellular signaling pathways. This review provides a basis for further research and development of clinical applications of curcumin for the treatment of newly emerged SARS-CoV-2. CONCLUSION AND CHALLENGES In this review, we have attempted an overview of the potential antiviral effects of curcumin that can be helpful for researchers to further investigate the potency of curcumin against the new emerging SARSCoV-2 infection. The ability of curcumin to modulate a wide range of molecular targets makes it a suitable candidate for the management of coronavirus infection. Curcumin may have beneficial effects against COVID-19 infection via its ability to modulate the various molecular targets that contribute to the attachment and internalization of SARS-CoV-2 in many organs, including the liver, cardiovascular system, and kidney. Curcumin could also modulate cellular signaling pathways such as inflammation, apoptosis, and RNA replication. Curcumin may also suppress pulmonary edema and fibrosis-associated pathways in COVID-19 infection. Despite the potential beneficial effects and safety profile of curcumin against various diseases, the limited bioavailability of this turmericderived compound, especially via oral administration may be a problematic issue (Anand, Kunnumakkara, Newman, & Aggarwal, 2007). Yang et al. demonstrated that intravenous administration of curcumin (10 mg/kg) resulted in better bioavailability in comparison to oral administration with a higher dose (500 mg/kg) (K. Y. Yang, Lin, Tseng, Wang, & Tsai, 2007). Several clinical trials have shown that the issue regarding the bioavailability of curcumin can be mitigated by administering higher concentrations within non-toxic limits (Kunnumakkara et al., 2019). In addition, many studies have suggested various ways to improve the bioavailability of curcumin such as manipulation and encapsulation of curcumin into micelles, liposomes, phospholipid complexes, exosomes, or polymeric nanocarrier formulation and also utilization of curcumin in combination with cellulosic derivatives, natural antioxidants, and a hydrophilic carrier (Jäger et al., 2014; Moballegh Nasery et al., 2020). Moreover, several studies have reported the synergistic therapeutic effects of curcumin in combination with other natural or synthetic compounds (Singh et al., 2013). Overall, the welldocumented anti-inflammatory and immunomodulatory effects of curcumin along with the evidence on the anti-fibrotic and pulmonoprotective effects of this phytochemical on the lung tissue make it a promising candidate for the treatment of COVID-19. Since curcumin is known to have strong inhibitory effects on NF-κB and several pro-inflammatory cytokines, it can be particularly helpful as an adjunct in reversing the fatal cytokine storm that occurs in serious cases of COVID-19. 6 ZAHEDIPOUR ET AL. To sum up, this review shows that curcumin as an antiviral and anti-inflammatory agent can be helpful for both prevention and treatment of new emerging coronavirus. However, well-designed clinical trials are needed to demonstrate the potential efficacy of curcumin against SARS-CoV-2 infection and its ensuing complications. Reference & Source Information: Read more on :

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