# An Overview of Japanese Encephalitis in Australia: Trends, Impact and Interventions
## 2 Host Invasion by JEV, Pathogenesis and Clinical Course  
The aetiological factor causing JE is an infection with a flavivirus that is transmitted from a mosquito belonging to the genus _Culex_ to a mammalian host [15]. While up to 14 species of mosquitoes have been identified as key transmission vectors, animals such as pigs and water birds, have been named amplifying and maintenance hosts of the virus, respectively [16; 17]. Therefore, viral transmission can often occur in agricultural locations, including rice or pig farms, and can be seasonal according to environmental conditions that favour the breeding of mosquitoes (e.g., tropical climates and floods). However, there is no evidence that the virus is transmitted from human-to-human or by eating the flesh from an infected animal [15]. In many cases, infected animals show only mild clinical disease, although some may experience an elevated temperature, jaundice, lethargy, weight loss, oedema, neurological problems (e.g., depression, dysphagia and impaired vision), or develop infertility [18]. The spherical-shaped virus is approximately 50 nm in diameter and is encapsulated by a lipid membrane consisting of structural proteins, such as the Envelope 'E' protein, precursor to membrane 'prM' protein and the capsid 'C' protein [16]. When the mosquito carrying the virus bites the host, the virus is delivered into the tissue and lymph nodes proximal to the contact site before entering circulation. The virus attaches to the host cell membrane and is endocytosed into the cytoplasm. During the replication process, the virus multiplies its genomic material, which translates into three structural and seven non-structural viral proteins. These proteins are then assembled into immature virions in the Golgi complex of the host cell before they are released as mature viruses [19]. The structural proteins consist of the capsid (C), pre-membrane (prM) and envelope (E) proteins, while the non-structural proteins (NS 1, 2A, 2B, 3, 4A, 4B and 5) drive viral replication where NS5 protein is key in suppressing interferon-dependent immune responses in the host [19; 20]. The route of virus invasion and replication mechanisms are detailed and illustrated in [PERSON] et al., [PERSON] et al. and [PERSON] et al. [19; 21; 22]. As replication actively occurs between 4 and 15 days, with an average incubation period of 7 days, the viral load becomes detectable in the blood during this time and the patient can either remain asymptomatic or may develop non-specific symptoms, such as diarrhoea, low-grade fever, nausea, headache, mylalgia and malaise, which can persist for several days [15]. In most cases, the host immune response is potent enough to eradicate the JEV infection over time and symptoms resolve. More severe symptoms such as seizures and changes in consciousness or behaviour may reveal that the virus has been carried to the central nervous system (CNS) via the bloodstream and penetrates the blood brain barrier (BBB) [15; 23]. Fatal consequences may also ensue due to the neurotoxic effects of the virus, often accompanied by an aggressive inflammatory response, neuronal cell death and glial scar formation [15; 21]. These symptoms can be attributed to the capacity of the virus to activate the inflammasome, a protein complex made up of innate immune system receptors and sensors [24]. Inflammasome activation triggers transcription of genes encoding NLR family pyrin domain containing 3 (NFLRP3), caspase 1, and Pycard, thus exerting pro-inflammatory and apoptotic effects in response to various stimuli, such as infections with pathogens, in an attempt to keep the host organism alive [24; 25]. Inflammosomes have been implicated in a series of autoimmunity and autoimmune disorders, including neurodegenerative diseases [24]. Hence, it is no surprise that the inflammasome plays a role in driving the pathological events observed in the brains of patients diagnosed with JE.