Abstract
The Flavivirus genus includes a number of important viruses that are pathogenic to humans and animals and are responsible for outbreaks across the globe. Integrins, a family of heterodimeric transmembrane molecules expressed in all nucleated cells mediate critical functions of cell physiology and cell cycle. Integrins were previously postulated to be involved in flavivirus entry and to modulate flavivirus replication efficiency. In the present study, mouse embryonic fibroblasts (MEF), lacking the expression of αVβ3 integrin (MEF-αVβ3−/−), were infected with four different flaviviruses, namely yellow fever virus (YFV), West Nile virus (WNV), Usutu virus (USUV) and Langat virus (LGTV). The effects of the αVβ3 integrin absence in double-knockout MEF-αVβ3−/− on flavivirus binding, internalization and replication were compared to the respective wild-type cells. Binding to the cell surface for all four flaviviruses was not affected by the ablation of αVβ3 integrin, whereas internalization of USUV and WNV was slightly affected by the loss of αVβ3 integrin expression. Most interestingly, the deletion of αVβ3 integrin strongly impaired replication of all flaviviruses with a reduction of up to 99% on virus yields and a strong reduction on flavivirus anti-genome RNA synthesis. In conclusion, our results demonstrate that αVβ3 integrin expression in flavivirus-susceptible cell lines enhances the flavivirus replication.
Highlights
Zoonotic flaviviruses are able to infect a broad diversity of hosts such as equines, birds, non-human primates and humans
We investigated the role of αVβ3 integrin in infection with West Nile virus (WNV) and three other flaviviruses using a mouse embryonic fibroblast (MEF) model lacking the expression of αVβ3 integrin
Our results demonstrated that the loss of αVβ3 integrin expression did neither impair flavivirus binding to the cell surface nor affected cell susceptibility
Summary
Zoonotic flaviviruses (family Flaviviridae; genus Flavivirus) are able to infect a broad diversity of hosts such as equines, birds, non-human primates and humans (reviewed in [1,2]). The antigenome RNA serves as template for the synthesis of new flavivirus genomic RNA (+ssRNA) [5] Their exceptional ability to infect a broad diversity of hosts raises speculations that flaviviruses use a common-shared receptor(s) to infect the host cell [8]. Integrins are a class of cell adhesion receptors and are expressed essentially in all nucleated cells from nematodes to mammals [11] They are heterodimeric transmembrane molecules composed of two non-covalently linked subunits: one alpha (α) and one beta (β) integrin subunit [12]. Flavivirus and integrin interactions were first reported by Chu et al, who demonstrated that αVβ3 integrin mediated WNV binding to and entry into CS-1 human melanoma cells. ΑVβ3 and αVβ5 integrin heterodimers were shown to be involved in Japanese encephalitis virus (JEV) and ZIKV infection and internalization, respectively, in human and mouse cell lines [30,31]. Ablation of αVβ3 integrin substantially affected flavivirus RNA replication suggesting that αVβ3 integrin represents an essential host cell factor, which promotes effective flavivirus replication
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