Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

Abstract

Dengue virus (DENV) infection can cause either self-limited dengue fever or hemorrhagic complications. Low platelet count is one of the manifestations of dengue fever. Megakaryocytes are the sole producers of platelets. However, the role of both host and viral factors in megakaryocyte development, maturation, and platelet production is largely unknown in DENV infection. PI3K/AKT/mTOR pathway plays a significant role in cell survival, maturation, and megakaryocyte development. We were interested to check whether pathogenic insult can impact this pathway. We observed decreased expression of most of the major key molecules associated with the PI3K/AKT/mTOR pathway in DENV infected MEG-01 cells. In this study, the involvement of PI3K/AKT/mTOR pathway in megakaryocyte development and maturation was confirmed with the use of specific inhibitors in infected MEG-01 cells. Our results showed that direct pharmacologic inhibition of this pathway greatly impacted megakaryopoiesis associated molecule CD61 and some essential transcription factors (GATA-1, GATA-2, and NF-E2). Additionally, we observed apoptosis in megakaryocytes due to DENV infection. Our results may suggest that DENV impairs PI3K/AKT/mTOR axis and molecules involved in the development and maturation of megakaryocytes. It is imperative to investigate the role of these molecules in the context of megakaryopoiesis during DENV infection to better understand the pathways and mechanisms, which in turn might provide insights into the development of antiviral strategies.

Effect of Human microRNA on Dengue Virus Genome: a cross-specie approach

“…mTOR in turn is responsible for megakaryocyte survival and its transformation to platelets 43 . Eventually it was noticed that two regulatory subunits of PI3K; p85 and p110ɑ are having reduced expression in DENV infected patients which might result in increased rate of megakaryocyte destruction 44 . The cluster also contains a subcluster of cytoskeleton proteins like actin and tubulin.…”

Let’s Get Physical: Flavivirus-Host Protein–Protein Interactions in Replication and Pathogenesis

“…Future efforts can be focused on investigating known uncharacterized physical interactions. The mTOR pathway is an important autophagy pathway that is differentially regulated during flavivirus infection ( Shives et al, 2014 ; Liang et al, 2016 ; Jordan and Randall, 2017 ; Sahoo et al, 2020 ; Lahon et al, 2021 ). Moreover, viral protein interactions with mTOR were also found using proteomic approaches ( Shah et al, 2018 ).…”

Repurposing Antifungals for Host-Directed Antiviral Therapy?

“…The activation of the PI3K/Akt/mTOR pathway is mediated through the phosphorylated and membrane-attached protein nsP3, which forms the viral replication complex upon virus internalization [83][84][85]. The activation of mTOR signaling is also fundamental for infection with the Flaviviridae West Nile virus (WNV), Japanese encephalitis virus (JEV) and dengue virus (DENV) [86][87][88]. Flaviviridae infection increases mTOR activity through a PI3K-dependent mechanism to maintain translation of its positive-sense RNA genome and also delays WNV-induced apoptosis [76,89,90].…”