The Immunopathogenesis of Neurotropic Flavivirus Infection

King, Nicholas J. C.; C, van Vreden; Rl, Terry; Dr, Getts; Aws, Yeung; Teague-Getts, M; Am, Davison; Deffrasnes, Céline; Munoz‐Erazo, Luis

doi:10.5772/22243

Cited by 4 publications

(2 citation statements)

References 136 publications

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“…JEV could cross the BBB via endothelial transcytosis and/or endothelial infection, as reported previously (24). However, there is little to no evidence in vivo for endothelial infection by flaviviruses (52). In our in vitro model, JEV infection of the endothelial cell line b.End3 was extremely low, even at an MOI as high as 10.…”

Section: Figmentioning

confidence: 62%

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

Wang

Lan

et al. 2015

J Virol

200

218

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Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage. In vitro studies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB. IMPORTANCEJapanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infection per se, but the inflammatory cytokines/ chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-␥) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-␥ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection. J apanese encephalitis (JE) is an acute zoonotic, mosquito-borne infectious disease caused by JE virus (JEV) infection. JEV is a single-stranded, positive-sense RNA virus, belonging to the genus Flavivirus of the family Flaviviridae (1, 2). JEV is a neurotropic virus and infection causes an acute encephalopathy. JE commonly affects children in the South Pacific regions of Asia (3, 4). Of nearly 70,000 cases of JE reported each year, ca. 20 to 30% of cases are fatal, and a high proport...

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Section: Figmentioning

confidence: 62%

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

Wang

Lan

et al. 2015

J Virol

200

218

View full text Add to dashboard Cite

show abstract

“…This study has also indicated that such a transcellular JEV transport may occur in pericytes as well [ 340 ]. Although JEV replication has not been consistently detected in vivo in BMECs of deceased JE patients or JEV-infected mice [ 209 , 327 , 329 , 341 ], because the virus may have been cleared at the time of analysis, it has been demonstrated in vitro by JEV infection experiments in cultured BMECs of humans and rats [ 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 ]. In these cultured BMECs, it is noted, though, that the level of JEV replication is unsustainably low and so has no or minimal effect on the cell viability, possibly due to the host antiviral/antiapoptotic responses [ 342 , 345 , 346 , 348 , 349 ].…”

Section: Mice: a Reliable Small-animal Model For Jev Researchmentioning

confidence: 99%

Mice as an Animal Model for Japanese Encephalitis Virus Research: Mouse Susceptibility, Infection Route, and Viral Pathogenesis

2023

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Japanese encephalitis virus (JEV), a zoonotic flavivirus, is principally transmitted by hematophagous mosquitoes, continually between susceptible animals and incidentally from those animals to humans. For almost a century since its discovery, JEV was geographically confined to the Asia-Pacific region with recurrent sizable outbreaks involving wildlife, livestock, and people. However, over the past decade, it has been detected for the first time in Europe (Italy) and Africa (Angola) but has yet to cause any recognizable outbreaks in humans. JEV infection leads to a broad spectrum of clinical outcomes, ranging from asymptomatic conditions to self-limiting febrile illnesses to life-threatening neurological complications, particularly Japanese encephalitis (JE). No clinically proven antiviral drugs are available to treat the development and progression of JE. There are, however, several live and killed vaccines that have been commercialized to prevent the infection and transmission of JEV, yet this virus remains the main cause of acute encephalitis syndrome with high morbidity and mortality among children in the endemic regions. Therefore, significant research efforts have been directed toward understanding the neuropathogenesis of JE to facilitate the development of effective treatments for the disease. Thus far, multiple laboratory animal models have been established for the study of JEV infection. In this review, we focus on mice, the most extensively used animal model for JEV research, and summarize the major findings on mouse susceptibility, infection route, and viral pathogenesis reported in the past and present, and discuss some unanswered key questions for future studies.

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PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

Spiteri

Ling

et al. 2022

Front. Immunol.

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PLX5622 is a CSF-1R inhibitor and microglia-depleting reagent, widely used to investigate the biology of this central nervous system (CNS)-resident myeloid population, but the indirect or off-target effects of this agent remain largely unexplored. In a murine model of severe neuroinflammation induced by West Nile virus encephalitis (WNE), we showed PLX5622 efficiently depleted both microglia and a sub-population of border-associated macrophages in the CNS. However, PLX5622 also significantly depleted mature Ly6Chi monocytes in the bone marrow (BM), inhibiting their proliferation and lethal recruitment into the infected brain, reducing neuroinflammation and clinical disease scores. Notably, in addition, BM dendritic cell subsets, plasmacytoid DC and classical DC, were depleted differentially in infected and uninfected mice. Confirming its protective effect in WNE, cessation of PLX5622 treatment exacerbated disease scores and was associated with robust repopulation of microglia, rebound BM monopoiesis and markedly increased inflammatory monocyte infiltration into the CNS. Monoclonal anti-CSF-1R antibody blockade late in WNE also impeded BM monocyte proliferation and recruitment to the brain, suggesting that the protective effect of PLX5622 is via the inhibition of CSF-1R, rather than other kinase targets. Importantly, BrdU incorporation in PLX5622-treated mice, suggest remaining microglia proliferate independently of CSF-1 in WNE. Our study uncovers significantly broader effects of PLX5622 on the myeloid lineage beyond microglia depletion, advising caution in the interpretation of PLX5622 data as microglia-specific. However, this work also strikingly demonstrates the unexpected therapeutic potential of this molecule in CNS viral infection, as well as other monocyte-mediated diseases.

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The Immunopathogenesis of Neurotropic Flavivirus Infection

Cited by 4 publications

References 136 publications

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

Mice as an Animal Model for Japanese Encephalitis Virus Research: Mouse Susceptibility, Infection Route, and Viral Pathogenesis

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production

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