INFLAMMATION IN JAPANESE ENCEPHALITIS - THE ROLE OF INTERLEUKIN 6

Japanese encephalitis virus is globally the most important insect-borne virus that infects the brain to cause encephalitis (swelling) and death. It is found in Asia, but is closely related to West Nile virus, which has caused outbreaks of encephalitis in America and Europe, and is spreading. There is no treatment for these diseases. I have been studying Japanese encephalitis for 10 years. Our recent studies on humans with Japanese encephalitis suggest that the body‘s own immune response to the infection may be doing more harm than good. In particular one of the proteins produced in the brain (IL-6) causes leakiness in the blood brain barrier (the lining between the blood vessels and the brain), allowing fluid into the brain, and causing brain swelling, and death. In this Fellowship I examine this problem in more detail by looking at the amount of virus, the amount of IL-6 protein, where the protein comes from, and what effect it has on the blood brain barrier. I also look at potential new treatments that stop this damaging chain of events. This work will point the way towards new treatments for Japanese encephalitis and related conditions.

Japanese encephalitis (JE) virus is the most important cause of epidemic viral encephalitis worldwide, with approximately 35-50,000 cases and 10-15,000 deaths annually. Although vaccines exist for JE, they are not available for most of the people in rural Asia that need them, because of issues over cost and production. Like the closely related West Nile virus, which has caused large outbreaks in southern Europe and the United States, this mosquito-borne flavivirus is spreading, and there is no established treatment. However there is increasing evidence that in JE, as in other RNA viral central nervous system (CNS) infections, a poorly regulated immune response may contribute to the pathogenesis - and this may be amenable to treatment.
We have recently found JE patients with high levels of IL-6 in the cerebrospinal fluid (CSF) are much more likely to die. This pro-inflammatory cytokine is produced by various CNS cells in response to viral infection. Whilst IL-6 may be protective at low levels, high levels can cause increased permeability of the blood brain barrier leading to cerebral oedema and death. Such high levels may be a response to the particular viral strain viral load, or they may be host specific.
In this Fellowship I will test the hypothesis that in JE over-production of IL-6 leads to increased blood brain barrier permeability and cerebral oedema, and makes an important contribution to death.
Using CSF, plasma and autopsy samples collected from humans with JE I will examine the relationship between IL-6, blood brain barrier function, and viral load. I will then use the well-established mouse model to address the same questions; but in the model I have the additional advantage of being able to control the viral strain and inoculum, and the host strain. In addition, I will use IL-6 knockout mice, and anti-IL-6 antibodies to further delineate the pathogenesis. Finally I will use this model to examine the effect of anti-inflammatory drugs on IL-6, blood brain barrier permeability, and fatality in the mouse model of JE. Anti-inflammatory drugs offer one of the best potentials for treatment of JE in humans, and these preclinical studies will be a critical prelude towards developing rationale treatment for this devastating disease