Abstract
BackgroundCurrently, no FDA-approved vaccines or treatments are available for Ebola virus disease (EVD), and therapy remains largely supportive. Ebola virus (EBOV) has broad tissue tropism and can infect a variety of cells including epithelial cells. Epithelial cells differ from most other cell types by their polarized phenotype and barrier function. In polarized cells, the apical and basolateral membrane domains are demarcated by tight junctions, and specialized sorting machinery, which results in a difference in composition between the two membrane domains. These specialized sorting functions can have important consequences for viral infections. Differential localization of a viral receptor can restrict virus entry to a particular membrane while polarized sorting can lead to a vectorial virus release. The present study investigated the impact of cell polarity on EBOV infection.MethodsCharacteristics of EBOV infection in polarized cells were evaluated in the polarized Caco-2 model grown on semipermeable transwells. Transepithelial resistance (TEER), which is a function of tight junctions, was used to assess epithelial cell polarization. EBOV infection was assessed with immunofluorescence microscopy and qPCR. Statistical significance was calculated using one-way ANOVA and significance was set at p < 0.05.ResultsOur data indicate that EBOV preferentially infects cells from the basolateral route, and this preference may be influenced by the resistance across the Caco-2 monolayer. Infection occurs without changes in cellular permeability. Further, our data show that basolateral infection bias may be dependent on polarized distribution of heparan sulfate, a known viral attachment factor. Treatment with iota-carrageenan, or heparin lyase, which interrupts viral interaction with cellular heparan sulfate, significantly reduced cell susceptibility to basolateral infection, likely by inhibiting virus attachment.ConclusionsOur results show cell polarity has an impact on EBOV infection. EBOV preferentially infects polarized cells through the basolateral route. Access to heparan sulfate is an important factor during basolateral infection and blocking interaction of cellular heparan sulfate with virus leads to significant inhibition of basolateral infection in the polarized Caco-2 cell model.
Highlights
No FDA-approved vaccines or treatments are available for Ebola virus disease (EVD), and therapy remains largely supportive
The present study investigates the impact of polarity on Ebola virus (EBOV) infection using the colorectal adenocarcinoma (Caco-2) cell polarized model
A polarized cell monolayer is characterized by a high Transepithelial resistance (TEER) and requires establishment of functional tight junctions between the cells [16]
Summary
No FDA-approved vaccines or treatments are available for Ebola virus disease (EVD), and therapy remains largely supportive. Polarized cells often act as barriers between the external environment and the underlying tissue Due to their asymmetric plasma membranes, these cells contain distinct apical or basolateral membranes and can impose an obstacle for virus infection and spread. Viruses subvert this in a variety of ways, including disruption of the tight junctional barrier or transcytosis to gain access to the basal tissue [1,2,3,4,5]. As of August 25 2018, the latest outbreak has caused 72 deaths with a total 111 cases [7] This highlights the fact that EBOV will remain a health threat in the near future, and development of therapeutics is urgently needed to effectively combat the virus
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