Japanese Encephalitis Virus: An Update on the Potential Antivirals and Vaccines

Abstract

Japanese encephalitis virus (JEV) is the causal agent behind Japanese encephalitis (JE), a potentially severe brain infection that spreads through mosquito bites. JE is predominant over the Asia-Pacific Region and has the potential to spread globally with a higher rate of morbidity and mortality. Efforts have been made to identify and select various target molecules essential in JEV's progression, but until now, no licensed anti-JEV drug has been available. From a prophylactic point of view, a few licensed JE vaccines are available, but various factors, viz., the high cost and different side effects imposed by them, has narrowed their global use. With an average occurrence of >67,000 cases of JE annually, there is an urgent need to find a suitable antiviral drug to treat patients at the acute phase, as presently only supportive care is available to mitigate infection. This systematic review highlights the current status of efforts put in to develop antivirals against JE and the available vaccines, along with their effectiveness. It also summarizes epidemiology, structure, pathogenesis, and potential drug targets that can be explored to develop a new range of anti-JEV drugs to combat JEV infection globally.

Keywords: Japanese encephalitis (JE); Japanese encephalitis virus (JEV); antiviral; drug; vaccine.

Figure 1

Cycle of the Japanese encephalitis virus (JEV) infection and amplification. Long-legged water birds, such as herons, storks, and ibises are the primary reservoirs and natural hosts for JEV. JEV-infected female mosquitoes, especially Culex tritaeniorhynchus, transmit the virus from wading water birds to other animals (pigs, cattle, and other hooved animals) and humans. Pigs act as secondary hosts where the virus becomes amplified at an optimum level and carries the infectious virion from one place to another (vector-free transmission). Female Culex mosquitos take up the virus from here and infect humans by biting them. The infected humans act as ‘dead-end’ hosts for the virus as JEV does not develop a titer high enough in the blood circulation to transmit through feeding mosquitoes.

Figure 2

Geographical distribution of JEV. The red part of the focused Indo-Pacific geographical regions and countries indicates where active JEV cases have been reported since its outbreak. The orange color shows the areas that have the highest risk of JEV infection in the near future. The epidemiological data of JEV was modified from https://www.who.int/news-room/fact-sheets/detail/japanese-encephalitis (accessed on 26 December 2022).

Figure 3

Genotypes of JEV and most affected countries. Based on the nucleotide sequences of the C/prM and E protein genes, JEV is classified into five genotypes as Genotype I, II, III, IV and V. A general representation of the origin of the various JEV genotypes, along with the countries/geographical areas where they are most abundant in or have the greatest impact (in the right side of the respective genotypes). The data represented is adapted from van den Hurk et al., 2022 [18], Gao X et. al., 2015 [31], Solomon T et. al., 2003 [32].

Figure 4

JEV structure, pathogenesis and potential drug targets. Schematic representation of JEV, comprising three structural proteins, namely capsid (C), precursor membrane (prM) and envelope (E), and seven non-structural (NS) proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5. N and C represent amino- and carboxyl-termini of the viral polyprotein. The pathogenesis of JEV begins with the binding of the virion onto the host receptor (DC-SIGN, heparin sulphate, Fc-receptor, etc.) and the internalization through clathrin-mediated endocytosis. Thereafter, the fusion of the viral particle/virion with endosome brings about a conformational change which releases the genetic material in an acidic environment. Very soon, the translation of viral RNA begins with the aid of host machinery onto a rough endoplasmic reticulum (ER) resulting in the synthesis of structural and non-structural proteins. In cognate, the NS viral proteins help in the formation of the replication complex and the genomic positive sense RNA becomes transcribed into complementary negative sense RNA. Furthermore, NS proteins (majorly NS3, NS4B and NS5) form a replication complex, and further several copies of positive sense genomic RNA become transcribed which are later encapsulated by the capsid protein, assembled with prM and E onto ER, and the assembled virus matures over the trans-Golgi network and finally the matured virions are released from the host cell through exocytosis. The inhibitory symbols indicate the potential drug targets for which efforts in the development of antivirals have been made so far, and research to diminish the JEV infection continues. Figure was originally created from BioRender.com (accessed on 26 December 2022).