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. 2023 Nov 9;17(11):e0011710.
doi: 10.1371/journal.pntd.0011710. eCollection 2023 Nov.

Influence of previous Zika virus infection on acute dengue episode

Cassia F Estofolete  1 , Alice F Versiani  1   2 , Fernanda S Dourado  1 , Bruno H G A Milhim  1 , Carolina C Pacca  1 , Gislaine C D Silva  1 , Nathalia Zini  1 , Barbara F Dos Santos  1 , Flora A Gandolfi  1 , Natalia F B Mistrão  1 , Pedro H C Garcia  1 , Rodrigo S Rocha  1 , Lee Gehrke  3   4 , Irene Bosch  3 , Rafael E Marques  5 , Mauro M Teixeira  6 , Flavio G da Fonseca  7   8 , Nikos Vasilakis  2   9   10   11   12 , Maurício L Nogueira  1   2
Affiliations

Influence of previous Zika virus infection on acute dengue episode

Cassia F Estofolete et al. PLoS Negl Trop Dis. .

Abstract

Background: The co-circulation of flaviviruses in tropical regions has led to the hypothesis that immunity generated by a previous dengue infection could promote severe disease outcomes in subsequent infections by heterologous serotypes. This study investigated the influence of antibodies generated by previous Zika infection on the clinical outcomes of dengue infection.

Methodology/principal findings: We enrolled 1,043 laboratory confirmed dengue patients and investigated their prior infection to Zika or dengue. Severe forms of dengue disease were more frequent in patients with previous Zika infection, but not in those previously exposed to dengue.

Conclusions/significance: Our findings suggest that previous Zika infection may represent a risk factor for subsequent severe dengue disease, but we did not find evidence of antibody-dependent enhancement (higher viral titer or pro-inflammatory cytokine overexpression) contributing to exacerbation of the subsequent dengue infection.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Screening of reactive peptides using monoclonal antibodies.
(A) Heatmap matrix of peptides assessed with monoclonal specific antibodies against ZIKV or DENV in an indirect IgG ELISA platform. Highest scores were selected for soluble synthesis. Peptide ZV-53 was not stable in soluble form and excluded from analysis. (B) IgG pepELISA for validation of soluble peptides. Serum samples from patients validated with PRNT were evaluated on plates with DV-15, DV-20, ZV-54, and ZV-107.
Fig 2
Fig 2. PepELISA and standard ELISA using validated samples.
A total of 170 serum samples validated with PRNT were tested on plates with: (A) DV-15; (B) DV-20; and (C) ZV-54. Peptide ZV-107 did not recognize any of the serum samples and was excluded from the further analysis. The same panel of samples were also tested with: (D) a mix of the NS1 protein of DENV-1, DENV-2, DENV-3, and DENV-4; and (E) To complete the positive controls, we tested the samples in plates coated with ZIKV NS1 protein. Gray area indicates the cutoff values based on the ROC curve specific for each antigen (Fig 3). Diagnostic performance analysis and cutoff values are presented in Table 1. Samples within the gray area are considered negative.
Fig 3
Fig 3. Performance of the pepELISA and standard NS1 ELISA using validated samples.
Receiver Operating Characteristic (ROC) curves of pepELISA for the peptides: (A) DV-15; (B) DV-20; (C) ZV-54; and standard ELISA against DENV NS1 mix (D), and ZIKV NS1 (E). Performance is demonstrated in True Positive Rate (Sensitivity %) versus False Positive Rate (100%—Specificity %).
Fig 4
Fig 4. Samples selection and case distribution according to serological sub cohort.
Criteria for inclusion into the cohort included laboratory-confirmed infection by RT-PCR and/or NS-1 ELISA or immunochromatographic method.
Fig 5
Fig 5. Expression of cytokines according to serological sub cohorts.
* p < 0.05; ** p< 0.01.
Fig 6
Fig 6. Inflammatory response models in acute dengue infection in primary and secondary dengue infection [left and middle panel] and proposed mechanism of response after previous Zika infection [right panel]. Created with BioRender.com.
See this image and copyright information in PMC

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