Cellular Organelles Reorganization During Zika Virus Infection of Human Cells

Abstract

Zika virus (ZIKV) is an enveloped positive stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae that emerged in recent decades causing pandemic outbreaks of human infections occasionally associated with severe neurological disorders in adults and newborns. The intracellular steps of flavivirus multiplication are associated to cellular membranes and their bound organelles leading to an extensive host cell reorganization. Importantly, the association of organelle dysfunction with diseases caused by several human viruses has been widely reported in recent studies. With the aim to increase the knowledge about the impact of ZIKV infection on the host cell functions, the present study was focused on the evaluation of the reorganization of three cell components, promyelocytic leukemia nuclear bodies (PML-NBs), mitochondria, and lipid droplets (LDs). Relevant human cell lines including neural progenitor cells (NPCs), hepatic Huh-7, and retinal pigment epithelial (RPE) cells were infected with the Argentina INEVH116141 ZIKV strain and the organelle alterations were studied by using fluorescent cell imaging analysis. Our results have shown that these three organelles are targeted and structurally modified during ZIKV infection. Considering the nuclear reorganization, the analysis by confocal microscopy of infected cells showed a significantly reduced number of PML-NBs in comparison to uninfected cells. Moreover, a mitochondrial morphodynamic perturbation with an increased fragmentation and the loss of mitochondrial membrane potential was observed in ZIKV infected RPE cells. Regarding lipid structures, a decrease in the number and volume of LDs was observed in ZIKV infected cells. Given the involvement of these organelles in host defense processes, the reported perturbations may be related to enhanced virus replication through protection from innate immunity. The understanding of the cellular remodeling will enable the design of new host-targeted antiviral strategies.

Molecular Events Occurring in Lipophagy and Its Regulation in Flaviviridae Infection

“…Similarly, the NS4A and NS4B proteins of ZIKV have also been found to induce lipophagy and thereby inhibit neurogenesis in human embryonic neural stem cells. The occurrence of ZIKV-induced lipophagy was similarly demonstrated in a recent study on the reorganization of organelles upon ZIKV virus infection of different cell lines, which found that the number and volume of LDs were reduced in ZIKV-infected cells, and this virus might induce LDs biogenesis, which stimulate the initial viral replication, and then trigger lipophagy to reduce LDs and release FFAs from these lipid structures (García et al, 2020). Meanwhile, the Japanese encephalitis virus (JEV) infection, analogous to other flaviviruses (DENV, WNV and ZIKV), decreased the number of LDs per cell indicating a link between lipid metabolism and virus replication (Sarkar et al, 2020).…”

Antiviral bioactivity of resveratrol against Zika virus infection in human retinal pigment epithelial cells

“…To explore the antiviral activity of RES against ZIKV in a retinal cell model, we employed ARPE-19, which is a spontaneously arising RPE cell line of male origin that retains normal karyology and hTERT-RPE-1 (from now on, abbreviated hRPE-1), which is a near-diploid human cell line of female origin. Both cell lines maintain the morphology and functions of in vivo human RPE cells [2,16].…”

“…Then, cells were fixed with 10% formaldehyde for 10 min, washed and stained with 0.1% crystal violet in 20% ethanol. Plaques were counted, and viral yield determined [16].…”

Interplay between RNA Viruses and Promyelocytic Leukemia Nuclear Bodies

“…Notably, SUMOylation of ZIKV NS5 is SIM-independent [ 32 ]. In NPCs, on the contrary, nuclear localization of NS5 resulted in a significant reduction in the number of PML NBs [ 33 ].…”