# An Overview of Japanese Encephalitis in Australia: Trends, Impact and Interventions
## 2 Host Invasion by JEV, Pathogenesis and Clinical Course
Additionally known as Apoptosis-associated speck-like protein containing a CARD (ASC), the Pycard protein is typically localised in the nuclei of macrophages and monocytes; however, following infection, it can move to the cytoplasm, endoplasmic reticulum and other sites where it performs its function in activating the inflammasome [33]. The function of ASC in assembling the NLRP3 inflammasome is believed to be a response to inflammatory cytokine stimulation [34]. In 2011, [PERSON] and [PERSON] suggested that JEV pathogenesis involved the activation of Pycard and various other pattern recognition receptors, including Toll-like receptors, C-type lectins, Cathepsin, Ill\(\beta\), and Caspases 1 and 4, in addition to the possible generation of inflammosomes when JEV infects the host [35]. By 2020, [PERSON] and [PERSON] demonstrated significant elevation of Pycard gene expression among patients with severe JE compared to those with milder symptoms. This observation is consistent with the upregulation of NLRP3 and Caspase 1 in severe cases, as mentioned above, thus suggesting a possible protective role of the NLRP3 inflammasome in the early stages of JEV infection. Similar pathways involving gene expression of Pycard and NLRP3 and inflammasomeactivation leading to neurological symptoms are also seen in West Nile Virus infections and, more recently, those caused by the SARS-CoV-2 (COVID-19) virus [36]. Taken together, viral infections caused by JEV activates molecular mechanisms driven by NLRP3 inflammasome activation, with [PERSON] and [PERSON] concluding that \"the variation in gene expression of inflammosomes may be associated with magnitude of JE pathogenesis and could be used as a probable marker for JE severity\" [25]. The cellular changes that ensue include the efflux of potassium or chloride ions and influx of calcium ions across the plasma membrane, lysosomal disruption, mitochondrial dysfunction, abnormal metabolic changes and trans-Golgi disassembly [27]. The combined effects of these processes lead to a rapid and inflammation-dependent kind of lytic cell death (i.e., pyrotosis) for the prompt removal of infected cells from the host, thereby triggering some of the common symptoms described below [27]. The clinical course of JE can take place in four stages. During the prodromal phase, the patient suffers from a high-grade fever, malaise and anorexia. The next stage, known as the \"acute stage\", results from increased intracranial pressure, caused by the build-up of inflammatory exudate in affected tissues. This stage is marked by more severe neurological symptoms consisting of loss of concentration or mental clarity, convulsion and impairment of sight, speech and/or hearing [16]. Up to 30% of patients succumb to death during this stage [16; 37]. The third stage, known as the \"defervescence phase\", occurs as fever subsides, but transient extrapyramidal features become prominent in patients exhibiting weakness of facial muscles, involuntary muscle contractions, rigidity and tremors [16]. The \"sequelae phase\" presents permanent neurological damage and approximately half of surviving patients experience one or more sequela: pyramidal weakness, convulsions, cognitive/language impairment, mental retardation and paralysis [16]. This final stage of JE affects children more than adults and those affected are unable to escape from at least some neurological symptoms and learning disabilities [16].