Abstract:Dengue virus (DENV) infection causes dengue fever in humans, which can lead to thrombocytopenia showing a marked reduction in platelet counts, and dengue hemorrhagic fever. The virus may cause thrombocytopenia either by destroying the platelets or by interfering with their generation via the process of megakaryopoiesis. MEG-01 is the human megakaryoblastic leukemia cell line that can be differentiated in vitro by phorbol-12-myristate-13-acetate (PMA) treatment to produce platelet-like-particles (PLPs). We have… Show more
“…It was also shown that DENV infection hampers polyploidy and production of PLT-like particles as well as expression of CD41, CD61, and CD42a surface markers in Meg-01 cells. 47 Collectively, our results suggest that DENV infection may induce ProT expression, resulting in suppression of megakaryopoiesis.…”
Section: Discussionmentioning
confidence: 67%
“… 70 Moreover, DENV infection impedes megakaryopoiesis in Meg-01 cells, which may be attributed to the binding of viral envelope protein to TAL-1, a megakaryopoiesis-specific transcription factor, and sequestration of TAL-1 in the cytoplasm. 47 Therefore, the mechanisms underlying dengue-induced impairment of megakaryopoiesis and thrombopoiesis are complicated and largely unclear. In the current study, our findings provide another possible mechanism, where DENV induces ProT overexpression to suppress megakaryopoiesis through promoting Nrf2 translocation to the nucleus and reducing ROS production.…”
“…It was also shown that DENV infection hampers polyploidy and production of PLT-like particles as well as expression of CD41, CD61, and CD42a surface markers in Meg-01 cells. 47 Collectively, our results suggest that DENV infection may induce ProT expression, resulting in suppression of megakaryopoiesis.…”
Section: Discussionmentioning
confidence: 67%
“… 70 Moreover, DENV infection impedes megakaryopoiesis in Meg-01 cells, which may be attributed to the binding of viral envelope protein to TAL-1, a megakaryopoiesis-specific transcription factor, and sequestration of TAL-1 in the cytoplasm. 47 Therefore, the mechanisms underlying dengue-induced impairment of megakaryopoiesis and thrombopoiesis are complicated and largely unclear. In the current study, our findings provide another possible mechanism, where DENV induces ProT overexpression to suppress megakaryopoiesis through promoting Nrf2 translocation to the nucleus and reducing ROS production.…”
“…4 A. In thrombocytopenia, only naive MEG-01 cells could be infected by DENV, and differentiated cells were resistant to virus infection/replication and it slowed the progress of megakaryopoiesis [ 37 ]. It has been observed that DENV infection enhances the activity of the Notch signaling pathway in the human system, and has been shown to limit the process of megakaryopoiesis.…”
Section: Denv and The Host Transcriptional Machinerymentioning
confidence: 99%
“… Fig. 4 DENV and host transcriptional regulation: A DENV Envelope sequesters the transcription factor TAL-1 in the cytoplasm, affecting its transcriptional function in the nucleus [ 37 ]. B Various factors involved in transcription such as GATA-1, GATA-2, and NF-E2, which participate in the process of megakaryopoiesis, are dysregulated during dengue infection [ 38 ].…”
Section: Denv and The Host Transcriptional Machinerymentioning
Dengue viruses (DENV) are positive-stranded RNA viruses belonging to the Flaviviridae family. DENV is the causative agent of dengue, the most rapidly spreading viral disease transmitted by mosquitoes. Each year, millions of people contract the virus through bites from infected female mosquitoes of the Aedes species. In the majority of individuals, the infection is asymptomatic, and the immune system successfully manages to control virus replication within a few days. Symptomatic individuals may present with a mild fever (Dengue fever or DF) that may or may not progress to a more critical disease termed Dengue hemorrhagic fever (DHF) or the fatal Dengue shock syndrome (DSS). In the absence of a universally accepted prophylactic vaccine or therapeutic drug, treatment is mostly restricted to supportive measures. Similar to many other viruses that induce acute illness, DENV has developed several ways to modulate host metabolism to create an environment conducive to genome replication and the dissemination of viral progeny. To search for new therapeutic options, understanding the underlying host-virus regulatory system involved in various biological processes of the viral life cycle is essential. This review aims to summarize the complex interaction between DENV and the host cellular machinery, comprising regulatory mechanisms at various molecular levels such as epigenetic modulation of the host genome, transcription of host genes, translation of viral and host mRNAs, post-transcriptional regulation of the host transcriptome, post-translational regulation of viral proteins, and pathways involved in protein degradation.
“…Moreover, MEG-01 cells have been shown to differentiate to mature megakaryocytes (MKs) in the presence of phorbol diesters and release platelet-like particles, and these differentiated forms showed a profound enhancement in expression of several MK-platelet-specific proteins including GPIIb/IIIa, fibrinogen, von Willebrand factor, factor XIIIa, β-thromboglobulin, and HLA class I antigen [ 27 , 28 ]. Based on these well-established megakaryoblastic phenotypes, MEG-01 cells have been commonly used for studies on differentiation of MKs and platelet-like particle production [ 29 , 30 , 31 , 32 , 33 ]. Recently, MEG-01 cells were established as a useful in vitro cellular model for platelet calcium signaling [ 34 ].…”
Thrombin stimulates platelets via a dual receptor system of protease-activated receptors (PARs): PAR1 and PAR4. PAR1 activation induces a rapid and transient signal associated with the initiation of platelet aggregation, whereas PAR4 activation results in a prolonged signal, required for later phases, that regulates the stable formation of thrombus. In this study, we observed differential signaling pathways for thrombin-induced PAR1 and PAR4 activation in a human megakaryoblastic leukemia cell line, MEG-01. Interestingly, thrombin induced both calcium signaling and morphological changes in MEG-01 cells via the activation of PAR1 and PAR4, and these intracellular events were very similar to those observed in platelets shown in previous studies. We developed a novel image-based assay to quantitatively measure the morphological changes in living cells, and observed the underlying mechanism for PAR1- and PAR4-mediated morphological changes in MEG-01 cells. Selective inhibition of PAR1 and PAR4 by vorapaxar and BMS-986120, respectively, showed that thrombin-induced morphological changes were primarily mediated by PAR4 activation. Treatment of a set of kinase inhibitors and 2-aminoethoxydiphenyl borate (2-APB) revealed that thrombin-mediated morphological changes were primarily regulated by calcium-independent pathways and PAR4 activation-induced PI3K/Akt and RhoA/ROCK signaling pathways in MEG-01 cells. These results indicate the importance of PAR4-mediated signaling pathways in thrombin-induced morphological changes in MEG-01 cells and provide a useful in vitro cellular model for platelet research.
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