scholarly journals Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Dong Chen ◽  
Zhiliang Duan ◽  
Wenhua Zhou ◽  
Weiwei Zou ◽  
Shengwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Replication ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Cd8 T Cells ◽  
Zika Virus ◽  
Encephalitis Virus ◽  
Protective Effects ◽  
Zikv Infection ◽  
Lethal Effects

Cross-reactive anti-flaviviral immunity can influence the outcome of infections with heterologous flaviviruses. However, it is unclear how the interplay between cross-reactive antibodies and T cells tilts the balance toward pathogenesis versus protection during secondary Zika virus (ZIKV) and Japanese encephalitis virus (JEV) infections. We show that sera and IgG from JEV-vaccinated humans and JEV-inoculated mice cross-reacted with ZIKV, exacerbated lethal ZIKV infection upon transfer to mice, and promoted viral replication and mortality upon ZIKV infection of the neonates born to immune mothers. In contrast, transfer of CD8+ T cells from JEV-exposed mice was protective, reducing the viral burden and mortality of ZIKV-infected mice and abrogating the lethal effects of antibody-mediated enhancement of ZIKV infection in mice. Conversely, cross-reactive anti-ZIKV antibodies or CD8+ T cells displayed the same pathogenic or protective effects upon JEV infection, with the exception that maternally acquired anti-ZIKV antibodies had no effect on JEV infection of the neonates. These results provide clues for developing safe anti-JEV/ZIKV vaccines.

scholarly journals Conserved amino acids 193–324 of non-structural protein 3 are a dominant source of peptide determinants for CD4+ and CD8+ T cells in a healthy Japanese encephalitis virus-endemic cohort

2004 ◽  
Vol 85 (5) ◽  
pp. 1131-1143 ◽  
Author(s):  
Priti Kumar ◽  
Paramadevanapalli Sulochana ◽  
Gejjehalli Nirmala ◽  
Maganti Haridattatreya ◽  
Vijaya Satchidanandam
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Cd8 T Cells ◽  
Encephalitis Virus ◽  
Structural Protein ◽  
Parent Protein ◽  
Ns3 Protein ◽  
Conserved Amino Acids

Our earlier identification of the non-structural protein 3 (NS3) of Japanese encephalitis virus (JEV) as a dominant CD4+ as well as CD8+ T cell-eliciting antigen in a healthy JEV-endemic cohort with a wide HLA distribution implied the presence of several epitopes dispersed over the length of the protein. Use of various truncated versions of NS3 in lymphocyte stimulation and interferon (IFN)-γ secretion assays revealed that amino acids (aa) 193–324 of NS3 were comparable with, if not superior to, the full-length protein in evoking Th1 responses. The potential of this 14·4 kDa stretch to stimulate IFN-γ production from both subtypes of T cells in a manner qualitatively and quantitatively similar to the 68 kDa parent protein suggested the presence within it of both class I and II epitopes and demonstrated that the entire immunogenicity of NS3 was focused on aa 193–324. Interestingly, this segment contained five of the eight helicase motifs of NS3. Analysis of variability of the NS3 protein sequence across 16 JEV isolates revealed complete identity of aa 219–318, which is contained within the above segment, suggesting that NS3-specific epitopes tend to cluster in relatively conserved regions that harbour functionally critical domains of the protein.

scholarly journals Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

2020 ◽  
Author(s):  
Ran Wang ◽  
Zida Zhen ◽  
Lance Turtle ◽  
Baohua Hou ◽  
Yueqi Li ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Cellular Immunity ◽  
Zika Virus ◽  
T Cell Response ◽  
Encephalitis Virus ◽  
Cross Protection ◽  
World Health ◽  
Effective Vaccine ◽  
Zikv Infection

AbstractZika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection, but did mediate antibody dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue into developing a novel bivalent vaccine against both ZIKV and JEV.ImportanceJapanese encephalitis is a controllable disease in many countries in Asia, especially in China, where many people have Japanese encephalitis virus (JEV) immunity due to extensive JEV vaccination campaigns or natural exposure. Live-attenuated SA14-14-2 strain is a safe and effective vaccine recommended by the World Health Organization and has been vaccinated more than 600 million doses since 1989. As the prevalence of Zika virus (ZIKV) and rising risk in above regions, the cross-reactive immune response between these two antigenically closely related flaviviruses, JEV and ZIKV, should also be fully recognized, which is presumed to be based on those ambiguous cross-reactive immunity between dengue virus and ZIKV. In this study, we found that JEV SA14-14-2 vaccine conferred cross-protection against ZIKV challenge in mice, which is mainly due to cellular immunity rather than neutralizing antibody response. However, specific protective components or cooperation between components warrant to be explored in subsequent experiments. In conclusion, this study can provide important evidence for those who live in JEV-endemic areas and are at risk for ZIKV infection.

scholarly journals Cell-mediated immune responses in healthy children with a history of subclinical infection with Japanese encephalitis virus: analysis of CD4+ and CD8+ T cell target specificities by intracellular delivery of viral proteins using the human immunodeficiency virus Tat protein transduction domain

2004 ◽  
Vol 85 (2) ◽  
pp. 471-482 ◽  
Author(s):  
Priti Kumar ◽  
Venkatramana D. Krishna ◽  
Paramadevanapalli Sulochana ◽  
Gejjehalli Nirmala ◽  
Maganti Haridattatreya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Structural Proteins ◽  
Healthy Children ◽  
Immunodeficiency Virus

Japanese encephalitis virus (JEV), a single-stranded positive-sense RNA virus of the family Flaviviridae, is the major cause of paediatric encephalitis in Asia. The high incidence of subclinical infections in Japanese encephalitis-endemic areas and subsequent evasion of encephalitis points to the development of immune responses against JEV. Humoral responses play a central role in protection against JEV; however, cell-mediated immune responses contributing to this end are not fully understood. The structural envelope (E) protein, the major inducer of neutralizing antibodies, is a poor target for T cells in natural JEV infections. The extent to which JEV non-structural proteins are targeted by T cells in subclinically infected healthy children would help to elucidate the role of cell-mediated immunity in protection against JEV as well as other flaviviral infections. The property of the Tat peptide of Human immunodeficiency virus to transduce proteins across cell membranes, facilitating intracellular protein delivery following exogenous addition to cultured cells, prompted us to express the four largest proteins of JEV, comprising 71 % of the JEV genome coding sequence, as Tat fusions for enumerating the frequencies of virus-specific CD4+ and CD8+ T cells in JEV-immune donors. At least two epitopes recognized by distinct HLA alleles were found on each of the non-structural proteins, with dominant antiviral Th1 T cell responses to the NS3 protein in nearly 96 % of the cohort. The data presented here show that non-structural proteins are frequently targeted by T cells in natural JEV infections and may be efficacious supplements for the predominantly antibody-eliciting E-based JEV vaccines.

scholarly journals 3′ cis-Acting Elements That Contribute to the Competence and Efficiency of Japanese Encephalitis Virus Genome Replication: Functional Importance of Sequence Duplications, Deletions, and Substitutions

2009 ◽  
Vol 83 (16) ◽  
pp. 7909-7930 ◽  
Author(s):  
Sang-Im Yun ◽  
Yu-Jeong Choi ◽  
Byung-Hak Song ◽  
Young-Min Lee
Keyword(s):  
Viral Replication ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Rna Replication ◽  
Encephalitis Virus ◽  
Protein Accumulation ◽  
Genomic Rna ◽  
Human Neuroblastoma ◽  
Lethal Mutant ◽  
Positive Strand Rna

ABSTRACT The positive-strand RNA genome of Japanese encephalitis virus (JEV) terminates in a highly conserved 3′-noncoding region (3′NCR) of six domains (V, X, I, II-1, II-2, and III in the 5′-to-3′ direction). By manipulating the JEV genomic RNA, we have identified important roles for RNA elements present within the 574-nucleotide 3′NCR in viral replication. The two 3′-proximal domains (II-2 and III) were sufficient for RNA replication and virus production, whereas the remaining four (V, X, I, and II-1) were dispensable for RNA replication competence but required for maximal replication efficiency. Surprisingly, a lethal mutant lacking all of the 3′NCR except domain III regained viability through pseudoreversion by duplicating an 83-nucleotide sequence from the 3′-terminal region of the viral open reading frame. Also, two viable mutants displayed severe genetic instability; these two mutants rapidly developed 12 point mutations in domain II-2 in the mutant lacking domains V, X, I, and II-1 and showed the duplication of seven upstream sequences of various sizes at the junction between domains II-1 and II-2 in the mutant lacking domains V, X, and I. In all cases, the introduction of these spontaneous mutations led to an increase in RNA production that paralleled the level of protein accumulation and virus yield. Interestingly, the mutant lacking domains V, X, I, and II-1 was able to replicate in hamster BHK-21 and human neuroblastoma SH-SY5Y cells but not in mosquito C6/36 cells, indicating a cell type-specific restriction of its viral replication. Thus, our findings provide the basis for a detailed map of the 3′ cis-acting elements in JEV genomic RNA, which play an essential role in viral replication. They also provide experimental evidence for the function of 3′ direct repeat sequences and suggest possible mechanisms for the emergence of these sequences in the 3′NCR of JEV and perhaps in other flaviviruses.

scholarly journals Nucleolar Protein B23 Interacts with Japanese Encephalitis Virus Core Protein and Participates in Viral Replication

2006 ◽  
Vol 50 (3) ◽  
pp. 225-234 ◽  
Author(s):  
Yoshimi Tsuda ◽  
Yoshio Mori ◽  
Takayuki Abe ◽  
Tetsuo Yamashita ◽  
Toru Okamoto ◽  
...  
Keyword(s):  
Viral Replication ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Core Protein ◽  
Encephalitis Virus ◽  
Nucleolar Protein ◽  
Virus Core ◽  
Protein B23
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