NLRP3 Inflammasome: Key Mediator of Neuroinflammation in Murine Japanese Encephalitis

Background: Japanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 b (IL-1b) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown. Methodology/Principal Findings: For our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1b and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines. Conclusion/Significance: Our results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1b an

Proteomic Analysis of Chikungunya Virus Infected Microgial Cells

Chikungunya virus (CHIKV) is a recently re-emerged public health problem in many countries bordering the Indian Ocean and elsewhere. Chikungunya fever is a relatively self limiting febrile disease, but the consequences of chikungunya fever can include a long lasting, debilitating arthralgia, and occasional neurological involvement has been reported. Macrophages have been implicated as an important cell target of CHIKV with regards to both their role as an immune mediator, as well evidence pointing to long term viral persistence in these cells. Microglial cells are the resident brain macrophages, and so this study sought to define the proteomic changes in a human microglial cell line (CHME-5) in response to CHIKV infection. GeLC-MS/MS analysis of CHIKV infected and mock infected cells identified some 1455 individual proteins, of which 90 proteins, belonging to diverse cellular pathways, were significantly down regulated at a significance level of p<0.01. Analysis of the protein profile in response to infection did not support a global inhibition of either normal or IRES-mediated translation, but was consistent with the targeting of specific cellular pathways including those regulating innate antiviral mechanisms

Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection

Background: Japanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-a (PPARa) agonist is known to resolve inflammation by repressing nuclear factor-kB (NF-kB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4. Methodology/Principal Findings: The neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80 % and brain LTB4 levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus. Conclusions/Significance: Fenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model o

Regulation of inflammation in Japanese encephalitis

Uncontrolled inflammatory response of the central nervous system is a hallmark of severe Japanese encephalitis (JE). Although inflammation is necessary to mount an efficient immune response against virus infections, exacerbated inflammatory response is often detrimental. In this context, cells of the monocytic lineage appear to be important forces driving JE pathogenesis

Simultaneous single epoch satellite clock modelling in global navigation satellite systems

In order to obtain high quality positions from navigation satellites, range errors have to be identified and either modelled or estimated. This thesis focuses on satellite clock errors, which are needed to be known because satellite clocks are not perfectly synchronised with navigation system time. A new approach, invented at UCL, for the simultaneous estimation, in a single epoch, of all satellite clock offsets within a Global Navigation Satellite System (GNSS) from range data collected at a large number of globally distributed ground stations is presented. The method was originally tested using only data from a limited number of GPS satellites and ground stations. In this work a total of 50 globally distributed stations and the whole GPS constellation are used in order to investigate more fully the capabilities of the method, in terms of both accuracy and reliability. A number of different estimation models have been tested. These include those with different weighting schemes, those with and without tropospheric bias parameters and those that include assumptions regarding prior knowledge of satellite orbits. In all cases conclusions have been drawn based on formal error propagation theory. Accuracy has been assessed largely through the sizes of the predicted satellite clock standard deviations and, in case of simultaneously estimating satellite positions, their error ellipsoids. Both internal and external reliability have been assessed as there are important contributions to integrity, something that is essential for many practical applications. It has been found that the accuracy and reliability of satellite clock offsets are functions of the number of known ground station clocks and distance from them, quality of orbits and quality of range measurement. Also the introduction of tropospheric zenith delay parameters into the model reduced both accuracy and reliability by amounts depending on satellite elevation angles

Comparison of plants used for skin and stomach problems in Trinidad and Tobago with Asian ethnomedicine

RefereedThis paper provides a preliminary evaluation of fifty-eight ethnomedicinal plants used in Trinidad and Tobago for skin problems, stomach problems, pain and internal parasites for safety and possible efficacy. Thirty respondents, ten of whom were male were interviewed from September 1996 to September 2000 on medicinal plant use for health problems. The respondents were obtained by snowball sampling, and were found in thirteen different sites, 12 in Trinidad and one in Tobago. The uses are compared to those current in Asia. Bambusa vulgaris, Bidens alba, Jatropha curcas, Neurolaena lobata, Peperomia rotundifolia and Phyllanthus urinaria are possibly efficacous for stomach problems, pain and internal parasites. Further scientific study of these plants is warranted