Interactions of human microglia cells with Japanese encephalitis virus

Abstract

BackgroundJapanese encephalitis virus (JEV) is a neurotropic flavivirus causing mortality and morbidity in humans. Severe Japanese encephalitis cases display strong inflammatory responses in the central nervous system and an accumulation of viral particles in specific brain regions. Microglia cells are the unique brain-resident immune cell population with potent migratory functions and have been proposed to act as a viral reservoir for JEV. Animal models suggest that the targeting of microglia by JEV is partially responsible for inflammatory reactions in the brain. Nevertheless, the interactions between human microglia and JEV are poorly documented.MethodsUsing human primary microglia and a new model of human blood monocyte-derived microglia, the present study explores the interaction between human microglia and JEV as well as the role of these cells in viral transmission to susceptible cells. To achieve this work, vaccine-containing inactivated JEV and two live JEV strains were applied on human microglia.ResultsLive JEV was non-cytopathogenic to human microglia but increased levels of CCL2, CXCL9 and CXCL10 in such cultures. Furthermore, human microglia up-regulated the expression of the fraktalkine receptor CX3CR1 upon exposure to both JEV vaccine and live JEV. Although JEV vaccine enhanced MHC class II on all microglia, live JEV enhanced MHC class II mainly on CX3CR1+ microglia cells. Importantly, human microglia supported JEV replication, but infectivity was only transmitted to neighbouring cells in a contact-dependent manner.ConclusionOur findings suggest that human microglia may be a source of neuronal infection and sustain JEV brain pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0675-3) contains supplementary material, which is available to authorized users.

Regulation of inflammation in Japanese encephalitis

“…Murine microglia is also productively infected by JEV for up to 16 weeks in vitro [ 45 ]. Although human microglia cells allow JEV replication, infectious virus is transmitted to susceptible cells in a cell-cell dependent manner [ 46 ].…”

“…Moreover, CXCL-8 has been measured from human macrophages [ 37 ] and IL-12, IFN-β and IFN-γ from murine macrophages [ 34 , 35 , 38 , 55 ]. Both human [ 46 ] and rodent [ 24 , 54 , 68 ] microglia produce CCL2 upon JEV exposure. In addition, human microglia produce CXCL9 and CXCL10 [ 46 ].…”

Cell-to-cell transport in viral families: faster than usual

“…A cell-to-cell transmission of viral RNA is alternative mechanism enabling the generation of new virus particles (Zhong et al, 2013). Human microglia incapable to generate infectious virus particles and production of microglia-associated JEV by target cells depends on cell contact (Lannes et al, 2017). Microglia may use virological synapses or membrane protrusions such as nanotubes and/or filopodia structures.…”

Research advancements in the neurological presentation of flaviviruses

“…In addition, human microglia infected by JEV can transmit the virus to neighbouring cells in a contact‐dependent manner . Further, microglia have been found to devour ZIKV‐infected NPCs and to transmit the virus to uninfected NPCs .…”

“…[35][36][37][38][39][40][41] In addition, human microglia infected by JEV can transmit the virus to neighbouring cells in a contact-dependent manner. 42 Further, microglia have been found to devour ZIKV-infected NPCs and to transmit the virus to uninfected NPCs. 43 This is consistent with the previously mentioned Trojan horse mechanism.…”