Megakaryopoiesis in Dengue virus infected K562 cell promotes viral replication which inhibits endomitosis and accumulation of ROS associated with differentiation

Abstract

AbstractIn the human host blood Monocytes and bone marrow Megakaryocytes are implicated as major sites supporting high replication. The human K562 cell line supports DENV replication and represent Megakaryocyte-Erythrocyte progenitors (MEP), replicating features of in vivo Megakaryopoiesis upon stimulation with Phorbol esters. In this article, we report results that indicate the mutual influence of Megakaryopoiesis and DENV replication on each other, through comparison of PMA-induced differentiation of either mock-infected or DENV-infected K562 cells. We present data showing PMA-induced differentiation to drastically increase DENV replication and a concomitant augmented secretion of infectious virus. Although the mechanism is not clear yet, we show that it is not through an increased uptake of virus by differentiated cells. On the other hand, DENV replication in cells undergoing PMA-induced differentiation, interferes with major differentiation markers of Megakaryopoiesis including activation of ERK1/2 MAP Kinase, endomitosis and surface expression of platelet-specific proteins without any drastic effect on cell death. Among signaling intermediaries of the JAK-STAT pathway, we observed infection associated degradation of SOC3 protein similar to earlier observations with STAT2. DENV infection leads to accumulation of Reactive-oxygen species (ROS) in different cells including K562. PMA-induced differentiation of uninfected K562 cells also leads to intracellular ROS accumulation. Interestingly, we observed ROS accumulation to be suppressed by concomitant DENV replication in K562 cells undergoing PMA-induced differentiation. This is the first report of a model system where DENV replication suppresses intracellular ROS accumulation. The implications of these results for Megakaryopoiesis and viral replication would be discussed.