Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

Kumar, Sanjay; Verma, Akanksha; Yadav, Pardeep; Dubey, Sumit Kumar; Azhar, Esam I.; Maitra, S. S.; Dwivedi, Vivek Dhar

doi:10.1007/s00705-022-05481-z

Cited by 27 publications

(20 citation statements)

References 209 publications

(241 reference statements)

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“…The RNA genome of JEV (≈11 kb) is modified at the 5 end cap with an m 7 GpppAm structure and mimics cellular mRNAs, except for lacking the polyadenylated tail [14]. The viral genome encodes a single 370 kDa polyprotein, which is subsequently cleaved by a combination of viral and host proteases to yield three structural (capsid, membrane, and envelope) and seven nonstructural (NS: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins [14,15]. Among the seven NS proteins, NS5 is the largest (~105 kDa) and conserved viral protein-housing a C-terminal RNAdependent RNA polymerase (RdRp) and an N-terminal guanylyltransferase (GTase) and methyltransferase (MTase) activity-and is associated with other viral proteins, host factors, and viral RNA to form the replication complex (RCs) [16,17].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Small Molecules from Echinacea angustifolia Targeting RNA-Dependent RNA Polymerase of Japanese Encephalitis Virus

Yadav

El‐Kafrawy

El-Daly

et al. 2022

Life

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The Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes viral encephalitis leading to neural damage, is a major threat in most Asian countries. The RNA-dependent RNA polymerase (RdRp) present in the viral genome is the key component for genome replication, making it an attractive target for antiviral drug development. In this study, the natural products from Echinacea angustifolia were retrieved for structure-based virtual screening against JEV–RdRp. The top six compounds (Echinacoside, Echinacin, Rutin, Cynaroside, Quercetagetin 7-glucoside, and Kaempferol-3-glucoside) were obtained based on the highest negative docking score, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and molecular interaction. The computational analysis of these selected compounds against the co-crystallized ligands, i.e., ATP and GTP, were performed. Further, 100 ns molecular dynamic simulation and post-free binding energy calculation of all the selected compounds complexed with JEV–RdRP were performed to check the stability of the complexes. The obtained results showed considerable stability and intermolecular interaction with native ligand-binding site residues of JEV–RdRp. Hence, selected natural compounds are admissible inhibitors of JEV–RdRp protein and can be considered for future antiviral drug development studies.

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Section: Introductionmentioning

confidence: 99%

Discovery of Small Molecules from Echinacea angustifolia Targeting RNA-Dependent RNA Polymerase of Japanese Encephalitis Virus

Yadav

El‐Kafrawy

El-Daly

et al. 2022

Life

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“…The impact of GV strains on public health is hard to predict based on current limited epidemiologic and pathophysiologic knowledge. Despite attempts to develop novel antiviral or drug repositioning for JEV, no drug is currently available and the vaccine remained the best option for the control of JE in humans [ 1 , 47 ]. A high percentage of the population in a JE endemic area already possesses cross-reactive immunity against GV strains through vaccination and natural infection.…”

Section: Discussionmentioning

confidence: 99%

“…Japanese encephalitis virus (JEV), a member of the Flaviviridae family, is an enveloped positive-sense RNA virus that can cause viral meningoencephalitis [ 1 , 2 ]. Japanese encephalitis (JE) is a prevalent infectious disease with about 67,900 cases annually in 24 Southeast Asian countries and in the Western Pacific region [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

Lee

Song

Seo

2022

J. Microbiol. Biotechnol.

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Genotype V (GV) StrainsJEV is currently subdivided into five genotypes mainly based on premembrane (prM) and envelope (E) gene sequences [11,12]. In 1952, a serologically distinct JEV, Muar, was isolated from the brain of a JE patient in Malaysia [13]. Based on a series of serologic studies using monoclonal antibodies, it was confirmed that Muar belongs to a separate antigenic group [14,15]. Early phylogenetic analysis also determined the Muar as a distinct GV [12,16]. An evolutionary study revealed that GV is the ancestor of other genotypes (i.e., GI~GIV) [17]. A follow-up study with phylogenetic simulation using whole genome sequence of all JEV genotypes also suggested that GV is nearest to the common ancestor and that GIV, GIII, GII, and GI evolved sequentially from GV [18].Because GV and GIV strains are relatively older, it seems natural to find GIII and GI more frequently from recent isolates. Indeed, GIII strains were common in early JEV studies but were gradually replaced by GI strains in most endemic areas [19,20]. In 2009, 57 years after isolation of the GV Muar, GV XZ0934 was isolated from Cx. tritaeniorhynchus in China [21]. When compared the whole genome between GV Muar and GV XZ0934, the similarity was 90.6% and 98.3% for nucleotide and amino acid sequences, respectively, reflecting a temporal gap between these two GV isolates [22]. Japanese encephalitis (JE) is a vaccine-preventable mosquito-borne disease caused by infection with the Japanese encephalitis virus (JEV). JEV has five genotypes, including genotype V (GV), which is considered ancestral to the other genotypes. The first GV strain, GV Muar, was isolated from a Malayan patient in 1952 and GV did not reappear for 57 years until GV XZ0934 was isolated from a mosquito sample in China. Since 2010, 21 GV strains have been identified in Republic of Korea (ROK). Both GV Muar and GV XZ0934 are more pathogenic than other GI/GIII strains and are serologically distinct. However, because the ROK's GV strains have not been experimentally tested, their characteristics are not known. Characterization of the ROK's isolates is needed to enable development of effective GV strain-based vaccines to protect against GV infections.

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“…After the furin cleavage of prM in pr m junction, the pr peptides remain bound to the E protein for preventing premature fusion when virions were transported across the acidic trans-Golgi network, followed by the release of pr-attached virions from the infected cells [ 22 ]. Markedly, the pr-attached virions and prM incomplete cleaved virions were exhibited as heterogeneous and dynamic infectious particles with a variation in tissue tropism, which increased the wide range of cells susceptible to ZIKV [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

A Reverse Mutation E143K within the PrM Protein of Zika Virus Asian Lineage Natal RGN Strain Increases Infectivity and Cytopathicity

Lin

Liao

et al. 2022

Viruses

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Zika virus (ZIKV) is a positive-sense single-stranded RNA virus in the Flaviviridae, which is classified into two different lineages Asian and African. The outbreak of ZIKV Asian lineage isolates in 2015–2016 is associated with the increase in cases with prenatal microcephaly and Guillain–Barré syndrome, and has sparked attention throughout the world. Genome sequence alignment and the analysis of Asian and African lineage isolates indicate that amino acid changes, particular in positively charged amino acid substitutions in the pr region of prM protein might involve a phenotypic change that links with the global outbreak of ZIKV Asian-lineage. The study generated and characterized the virological properties of wild type and mutants of single-round infectious particles (SRIPs) and infectious clones (i.c.s) of ZIKV Asian-lineage Natal RGN strain, and then identified the function of amino acid substitutions at the positions 139 [Asn139→Ser139 (N139S)] and 143 [Glu143→Lys143 (E143K)] in ZIKV polyproteins (located within the pr region of prM protein) in the infectivity and cytopathogenicity. The E143K SRIP and i.c. of Natal RGN strain exhibited relatively higher levels of cytopathic effect, EGFP reporter, viral RNA and protein synthesis, and virus yield in three types of human cell lines, TE617, SF268 and HMC3, compared to wild type (WT), N139S SRIPs and i.c.s, which displayed more efficiency in replication kinetics. Additionally, E143K Natal RGN i.c. had greater activities of virus attachment and entry, yielded higher titers of intracellular and extracellular virions, and assembled the E proteins near to the plasma membrane in infected cells than the other i.c.s. The results indicate that the positively charged amino acid residue Lys143, a conserved residue in the pr region of prM of ZIKV African lineages, plays a crucial role in viral replication kinetics, including viral attachment, entry, assembly and egress. Thus, the negatively charged amino acid residue Glu143 within the pr region of prM leads to an alteration of the phenotypes, in particular, a lower replication efficiency of ZIKV Asian-lineage isolates with the attenuation of infectivity and cytopathicity.

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Molecular pathogenesis of Japanese encephalitis and possible therapeutic strategies

Cited by 27 publications

References 209 publications

Discovery of Small Molecules from Echinacea angustifolia Targeting RNA-Dependent RNA Polymerase of Japanese Encephalitis Virus

Discovery of Small Molecules from Echinacea angustifolia Targeting RNA-Dependent RNA Polymerase of Japanese Encephalitis Virus

Emerging Japanese Encephalitis Virus Genotype V in Republic of Korea

A Reverse Mutation E143K within the PrM Protein of Zika Virus Asian Lineage Natal RGN Strain Increases Infectivity and Cytopathicity

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