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.
Highlights
Zika virus (ZIKV) is an enveloped positive stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae, which includes other relevant pathogenic arboviruses such as dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and West Nile virus (WNV)
Promyelocytic leukemia nuclear bodies are highly dynamic nuclear structures that involve the entry of enzymes and substrates to carry out various cellular functions
It is well established that ZIKV replicates in neural progenitor cells (NPCs) (Qian et al, 2016) provoking alterations of cellular pathways which are thought to promote Zika’s congenital syndrome brain abnormalities (Calvet et al, 2016; Mlakar et al, 2016; Yockey et al, 2016; Chavali et al, 2017)
Summary
Zika virus (ZIKV) is an enveloped positive stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae, which includes other relevant pathogenic arboviruses such as dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and West Nile virus (WNV). The infrequent human infections reported in Africa and Asia were asymptomatic or generally associated with very mild clinical manifestations (Gubler et al, 2017) This situation dramatically changed in more recent years when ZIKV spread across Asia first to the Pacific Islands and was introduced into Brazil in 2014. A hostdirected compound has lower potential to select for resistant variants For this antiviral strategy, the basic aspects of the virus-cell interaction must be elucidated. All the intracellular steps of flavivirus multiplication are associated to cellular membranes and their bound organelles, leading to an extensive host cell reorganization. The targeting of cellular organelles in ZIKV infection has been proved by studies of intracellular localization of viral proteins through immunocytochemistry and proteomics analysis (Hou et al, 2017; Coyaud et al, 2018). We evaluated the effect on the organization of two cytoplasmic organelles participating in the host defense, mitochondria and LDs, in ZIKV infected human cells
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