Signs that develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions, and a raised body temperature between 38–41 °C (100.4–105.8 °F).

[7] Increased microglial activation following Japanese encephalitis infection has been found to influence the outcome of viral pathogenesis.

Microglia are the resident immune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms.

Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), which can cause toxic effects in the brain.

Additionally, other soluble factors such as neurotoxins, excitatory neurotransmitters, prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.

[8] In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain, closely followed by that in the thalamus.

An overall induction of differential expression of proinflammatory cytokines and chemokines from different brain regions during a progressive Japanese encephalitis infection was also observed.Shukla M, Garg A, Dhole TN, Chaturvedi R (2023).

"Exaggerated levels of some specific TLRs, cytokines and chemokines in Japanese encephalitis infected BV2 and neuro 2A cell lines associated with worst outcome".

Although the net effect of the proinflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a non-regenerating organ such as the brain, a dysregulated innate immune response would be deleterious.

It has been noted that Japanese encephalitis infects the lumen of the endoplasmic reticulum (ER)[13][14] and rapidly accumulates substantial amounts of viral proteins.

Serum collected within 10 days of illness onset may not have detectable IgM, and the test should be repeated on a convalescent sample.

The high cost of this vaccine, which is grown in live mice, means that poorer countries could not afford to give it as part of a routine immunization program.

[citation needed] A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity.

A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in Japanese encephalitis infection of the brain.

This transcriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapies for Japanese encephalitis.

[citation needed] Countries that have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, South Korea, Singapore, Japan, Taiwan and Thailand.

[citation needed] In 2022, the notable increase in the distribution of the virus in Australia due to climate change became a concern to health officials as the population has limited immunity to the disease and the presence of large numbers of farmed and feral pigs could act as reservoirs for the virus.

[7] In February 2022, Japanese encephalitis was detected and confirmed in piggeries in Victoria, Queensland and New South Wales.

By October 2022, the outbreak in eastern mainland Australia had caused 42 symptomatic human cases of the disease, resulting in seven deaths.

Although this challenges the long-held belief that neurons are immunologically quiescent, an improved understanding of the proinflammatory effects responsible for immune-mediated control of viral infection and neuronal injury during Japanese encephalitis infection is an essential step for developing strategies for limiting the severity of CNS disease.

[37] A number of drugs have been investigated to either reduce viral replication or provide neuroprotection in cell lines or studies in mice.

However, it wasn’t until 1924, during a major outbreak involving over 6,000 cases, that JE’s severity and potential for widespread impact became apparent.

By 1995, JE cases had reached Papua New Guinea and northern Australia (specifically the Torres Strait), representing the virus's southernmost range.

According to the World Health Organization (WHO), JE is also endemic to the Western Pacific Islands, but cases are rare, possibly due to an enzootic cycle that does not sustain continuous viral transmission.