Linear epitope mapping in the E and NS1 proteins of dengue and Zika viruses: Prospection of peptides for vaccines and diagnostics

Aquino, Victor Hugo; Fumagalli, Marcilio J.; Silva, Angélica; de Moura Negrini, Bento Vidal; Rojas, Alejandra; Guillen, Yvalena; Bernal, Cynthia; Figueiredo, Luiz Tadeu Moraes

doi:10.1371/journal.pone.0292451

Cited by 2 publications

(3 citation statements)

References 43 publications

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“…One key finding from our work is the increased cross-reactivity to both DENV-EDIII domain and NS1 (but not to similar ZIKV regions) in absence of CD4 + T cells before the primary DENV infection but not before the ZIKV challenge. The fact that the cross reactivity was identified against both the structural EDIII domain and the NS1 protein agrees with the finding that CD4 + T cell epitopes in humans are skewed toward recognition of viral components that are also targeted by B lymphocytes and, from here, guiding the production of Abs mainly against the structural proteins (Rivino et al, 2013) or NS1 protein having also T and B cells epitopes (Aquino et al, 2023;Beicht et al, 2023;Perera et al, 2024;Shu et al, 2000). We do not completely understand why the cross-reactivity was higher against the NS1 protein than to the EDIII domain, but the factors responsible for directing CD4 + T cell to similar sites at the virus protein surface (or to NS1) in different flaviviruses are unknown (Aberle et al, 2018).…”

Section: Discussionsupporting

confidence: 86%

“…Most humoral immunity epitopes are located within the domains of the DENV envelope (E) protein, while cellular immunity epitopes are located on the NS proteins (Pinheiro et al, 2021; Rothman, 2010). Additionally, the NS1 protein is particularly interesting and unique, as it is a protein produced and secreted during viral replication, which make it highly immunogenic (Zhang et al, 2023) inducing significant levels of anti-NS1 Abs in DENV-and ZIKV-infected individuals (Aquino et al, 2023; Castro-Trujillo et al, 2023; Churdboonchart et al, 1991; Costa et al, 2007; Petphong et al, 2023). It is documented that DENV E and NS1 proteins equally score 4 – out of the 10 proteins – in an immunogenicity score (Weiskopf et al, 2016), and some reports have pointed NS1 as a target antigen for the development of DENV vaccines (Costa et al, 2007; Costa et al, 2006; Henchal et al, 1988; Wan et al, 2014), while others suggest a role for this protein in the pathogenesis (Perera et al, 2024; Shu et al, 2000; Zhang et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

“…Some evidence from animal models and humas suggest that prior DENV immunity has a protective role in secondary ZIKV infection (Ana Carolina Bernardes Terzian, 2017;Breitbach et al, 2019;McCracken et al, 2017;Pantoja et al, 2017). Other works propose that prior DENV infection may increase ZIKV disease severity (Bardina et al, 2017;Crooks et al, 2021;Katzelnick et al, 2020b;Katzelnick et al, 2021). Intermediate pre-existing levels of naturally acquired anti-DENV or anti-ZIKV antibodies (Abs) were found to be associated with enhancement of symptomatic and severe DENV.…”

Section: Introductionmentioning

confidence: 99%

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CD4+ T Cell Depletion Before Primary Dengue and/or Secondary Zika Infection Reveals Mechanistic Correlates of Antibody Functionality in Rhesus Macaques

Serrano-Collazo,

Miranda,

Cruz

et al. 2024

Preprint

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Dengue (DENV) virus and Zika virus (ZIKV) are two flaviviruses of major public health concern. One drawback designing effective vaccines is our limited understanding of the mechanisms ruling protection or harm among DENV serotypes, or between DENV and ZIKV. Here, we depleted rhesus macaques of CD4+T cellsin vivobefore primary DENV infection and/or secondary ZIKV challenge to recreate a sub-optimal priming of the humoral immune response. Our results support that CD4+T cells are needed to induce a quantitative and type-specific effective humoral immune response against primary DENV, but also against secondary ZIKV in DENV-experimented subjects. Our results also indicate a limited contribution of the DENV-Memory B cells to anti-ZIKV response. Furthermore, our results suggest that a suboptimal B cell priming during a primary DENV infection does differentially impact different antibody (Abs) properties. While binding or neutralization of ZIKV or DENV during a subsequent exposure to ZIKV is not affected by the lack of CD4+T - B cells interaction during a primary DENV infection, that interaction is critical to guarantee the Abs specificity. Also, we found that depleting CD4+T cells before DENV primary infection but not before ZIKV challenge significantly increases Abs cross-reactivity against DENV-EDIII domain and DENV-NS1 protein but not against ZIKV-EDIII domain or NS1 protein. Furthermore, there was more cross-reactivity among the DENV-NS1 proteins than against DENV-EDIII domains, suggesting that during a primary DENV infection CD4+T cells have a different weight in the responses against EDIII domain and NS1 protein. The proper Abs binding and neutralization with increased cross-reactivity profile was associated with limited frequency of circulating peripheral T helper cells (pTfh) with T helper 1 phenotype (CD4+/CXCR5+/CXCR3+) and expressing markers related to B cell activation (CXCR5+/CXCR3+/PD-1+/ICOS+) in the group depleted of CD4+T cells only before primary DENV infection. However, memory B cells – but not Antibody Secreting Cells (ASC) activation 7 days after the infection – positively correlate with those two populations of pTfh. Finally, when Abs cross-reactivity values were incorporated in a Principal Component Analysis (PCA), the DENV-CD4+T depleted group separates from the other two groups with similar Abs binding and neutralization profiles. Our result strongly suggests that during a heterologous sequential DENV/ZIKV infections Abs binding, and neutralization, may be regulated by different factors than their specificity. Before, the induction of cross-neutralizing Abs has been described in the context of secondary DENV infection. Here, for the first time, we are reproducing the experimental conditions leading to the generation of such Abs populationin vivo. In summary, we show that suboptimal immune priming during a primary flavivirus infection has functional consequences during a secondary heterologous infection. These results have huge implications understanding the immune response to DENV vaccines (and maybe ZIKV), including why an optimal vaccine or natural-induced neutralizing response not necessarily protects or enhances pathogenesis during a subsequent natural heterologous exposure.

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