Early Events in Japanese Encephalitis Virus Infection: Viral Entry

Abstract

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic flavivirus, is an enveloped positive-strand RNA virus that can cause a spectrum of clinical manifestations, ranging from mild febrile illness to severe neuroinvasive disease. Today, several killed and live vaccines are available in different parts of the globe for use in humans to prevent JEV-induced diseases, yet no antivirals are available to treat JEV-associated diseases. Despite the progress made in vaccine research and development, JEV is still a major public health problem in southern, eastern, and southeastern Asia, as well as northern Oceania, with the potential to become an emerging global pathogen. In viral replication, the entry of JEV into the cell is the first step in a cascade of complex interactions between the virus and target cells that is required for the initiation, dissemination, and maintenance of infection. Because this step determines cell/tissue tropism and pathogenesis, it is a promising target for antiviral therapy. JEV entry is mediated by the viral glycoprotein E, which binds virions to the cell surface (attachment), delivers them to endosomes (endocytosis), and catalyzes the fusion between the viral and endosomal membranes (membrane fusion), followed by the release of the viral genome into the cytoplasm (uncoating). In this multistep process, a collection of host factors are involved. In this review, we summarize the current knowledge on the viral and cellular components involved in JEV entry into host cells, with an emphasis on the initial virus-host cell interactions on the cell surface.

RIPK3 Promotes JEV Replication in Neurons via Downregulation of IFI44L

“…JEV is both neurovirulent and neuroinvasive and can lead to severe encephalitis (Lannes et al, 2017). Glycoprotein E mediates JEV entry through attachment and endocytosis, followed by membrane fusion and uncoating (Wang et al, 2017;Yun and Lee, 2018). Pattern recognition receptors (PRRs), such as retinoic acidinducible gene 1-like receptors (RIG-I) and Toll-like receptor 3 (TLR3), in infected cells can recognize viral components and induce the production of interferons (IFNs), which then drive the expression of various IFN-stimulated genes (ISGs) through the IFN receptor (IFNR)/Janus kinase (Jak1)/tyrosine kinase (Tyk)2/signal transducer and activator of transcription (STAT)1/STAT2 pathway to fight against virus invasion (Liu et al, 2013;Han et al, 2014).…”

CRISPR screening of porcine sgRNA library identified host factors essential for Japanese encephalitis virus replication

“…While several inactivated and live vaccines are used to prevent JEV infection, no antiviral drugs are available for the treatment of JEV-related diseases 4,5 . Despite achievements in control and prevention of JEV infection, this disease remains a major public health concern in Northern Oceania and in South, East, and Southeast Asia, and is viewed as an emerging global pathogen 6 .…”

“…The JEV infection cycle starts with binding to unknown cellular receptors and attachment factors 6,13 , followed by viral entry to enable replication. Subsequently, the JEV RNA genome is replicated, viral particles are matured and packaged, and released from cells.…”

CRISPR screening of porcine sgRNA library identifies host factors associated with Japanese encephalitis virus replication

“…While several inactivated and live vaccines are used to prevent JEV infection, no antiviral drugs are available for the treatment of JEV-related diseases 4,5 . Despite achievements in control and prevention of JEV infection, this disease remains a major public health concern in Northern Oceania and in South, East, and Southeast Asia, and it's viewed as an emerging global pathogen 6 .…”

“…The JEV infection cycle starts with binding to unknown cellular receptors and attachment factors 6,13 , followed by viral entry to enable replication. Subsequently, the JEV RNA genome is replicated, viral particles are matured, packaged, and released from cells.…”