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A fatal case of dengue hemorrhagic fever associated with dengue virus 4 (DENV-4) in Brazil: genomic and histopathological findings

Abstract

Dengue infection is the most prevalent arthropod-borne viral disease in subtropical and tropical regions, whose primary vector is Aedes aegypti mosquitoes. The mechanisms of dengue virus (DENV) pathogenesis are little understood because we have no good disease models. Only humans develop symptoms (dengue fever, DF, or dengue hemorrhagic fever, DHF) and research has been limited to studies involving patients. Samples from serum, brain, cerebellum, heart, lungs, liver, and kidneys from a 13-year-old male patient that died with hemorrhagic manifestations were sent for differential diagnosis at Adolfo Lutz, using both classical virological methods (RT-qPCR, virus isolation, ELISA, and hemagglutination inhibition test) and immunohistochemistry (IHQ). A DENV serotype 4 was detected by a DENV multiplex RT-qPCR, and the C6/36 cell supernatant was used for NGS using Minion. Lesions were described in the heart, liver, lung, and kidney with positive IHQ in endothelial cells of the brain, cerebellum, heart, and kidney, and also in hepatocytes and Kuppfer cells. A whole genome was obtained, revealing a DENV-4 genotype II, with no evidence of secondary dengue infection.

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Acknowledgements

We thank Núcleo de Doenças de Transmissão Vetorial Staff Antonia, Ivani Bisordi and Adriana Yurika Maeda, for DENV diagnosis.

Funding

This study was supported by CADDE Project (FAPESP 2018/14389–0) and Secretaria de Estado de Saúde de São Paulo (SES-SP).

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Contributions

Manuscript preparation: MSC, JMG; phylogenetic analysis: MSC; obtained funding and study supervision: ECS; sequencing: MSC, TMC, IMC, FS; histopathology and IHC: CCP, JMG, NCCRS, RR; protein analyses: DFLN. All authors reviewed, contributed to, and approved the final version of the manuscript.

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Correspondence to Mariana Sequetin Cunha.

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CADDE project GB04-BF07 (for etiological research).

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Cunha, M.S., de Moura Coletti, T., Guerra, J.M. et al. A fatal case of dengue hemorrhagic fever associated with dengue virus 4 (DENV-4) in Brazil: genomic and histopathological findings. Braz J Microbiol (2022). https://doi.org/10.1007/s42770-022-00784-4

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  • DOI: https://doi.org/10.1007/s42770-022-00784-4

Keywords

  • Dengue virus
  • Immunohistochemistry
  • Whole-genome sequencing
  • Phylogeny