Nanosensors based on LSPR are able to serologically differentiate dengue from Zika infections

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Abstract

The Flaviviridae virus family was named after the Yellow-fever virus, and the latin term flavi means “of golden color”. Dengue, caused by Dengue virus (DENV), is one of the most important infectious diseases worldwide. A sensitive and differential diagnosis is crucial for patient management, especially due to the occurrence of serological cross-reactivity to other co-circulating flaviviruses. This became particularly important with the emergence of Zika virus (ZIKV) in areas were DENV seroprevalence was already high. We developed a sensitive and specific diagnostic test based on gold nanorods (GNR) functionalized with DENV proteins as nanosensors. These were able to detect as little as one picogram of anti-DENV monoclonal antibodies and highly diluted DENV-positive human sera. The nanosensors could differentiate DENV-positive sera from other flavivirus-infected patients, including ZIKV, and were even able to distinguish which DENV serotype infected individual patients. Readouts are obtained in ELISA-plate spectrophotometers without the need of specific devices.

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Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests.

Christopher Florkowski (2008)

* Diagnostic accuracy studies address how well a test identifies the target condition of interest. * Sensitivity, specificity, predictive values and likelihood ratios (LRs) are all different ways of expressing test performance. * Receiver operating characteristic (ROC) curves compare sensitivity versus specificity across a range of values for the ability to predict a dichotomous outcome. Area under the ROC curve is another measure of test performance. * All of these parameters are not intrinsic to the test and are determined by the clinical context in which the test is employed. * High sensitivity corresponds to high negative predictive value and is the ideal property of a "rule-out" test. * High specificity corresponds to high positive predictive value and is the ideal property of a "rule-in" test. * LRs leverage pre-test into post-test probabilities of a condition of interest and there is some evidence that they are more intelligible to users.

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Immune response to dengue virus and prospects for a vaccine.

Stephen Whitehead, Patrick B. Murphy (2010)

Dengue virus (DENV) is a mosquito-borne member of the Flavivirus genus and includes four serotypes (DENV-1, DENV-2, DENV-3, and DENV-4), each of which is capable of causing dengue fever and dengue hemorrhagic fever/dengue shock syndrome. Serious disease can be seen during primary infection but is more frequent following second infection with a serotype different from that of a previous infection. Infection with wild-type DENV induces high-titered neutralizing antibody that can provide long-term immunity to the homotypic virus and can provide short-term immunity (only several months duration) to a heterotypic DENV. The high level of virus replication seen during both secondary infection with a heterotypic virus and during primary DENV infection in late infancy is a direct consequence of antibody-dependent enhancement of replication. This enhanced virus replication is mediated primarily by preexisting, nonneutralizing, or subneutralizing antibodies to the virion surface antigens that enhance access of the virion-antibody complex to FcγR-bearing cells. Vaccines will need to provide long-term protection against each of the four DENV serotypes by inducing neutralizing antibodies, and live, attenuated and various nonliving virus vaccines are in development.

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Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II.

Chih-Yun Lai, Wen-Yang Tsai, Su-Ru Lin … (2008)

The antibody response to the envelope (E) glycoprotein of dengue virus (DENV) is known to play a critical role in both protection from and enhancement of disease, especially after primary infection. However, the relative amounts of homologous and heterologous anti-E antibodies and their epitopes remain unclear. In this study, we examined the antibody responses to E protein as well as to precursor membrane (PrM), capsid, and nonstructural protein 1 (NS1) of four serotypes of DENV by Western blot analysis of DENV serotype 2-infected patients with different disease severity and immune status during an outbreak in southern Taiwan in 2002. Based on the early-convalescent-phase sera tested, the rates of antibody responses to PrM and NS1 proteins were significantly higher in patients with secondary infection than in those with primary infection. A blocking experiment and neutralization assay showed that more than 90% of anti-E antibodies after primary infection were cross-reactive and nonneutralizing against heterologous serotypes and that only a minor proportion were type specific, which may account for the type-specific neutralization activity. Moreover, the E-binding activity in sera of 10 patients with primary infection was greatly reduced by amino acid replacements of three fusion loop residues, tryptophan at position 101, leucine at position 107, and phenylalanine at position 108, but not by replacements of those outside the fusion loop of domain II, suggesting that the predominantly cross-reactive anti-E antibodies recognized epitopes involving the highly conserved residues at the fusion loop of domain II. These findings have implications for our understanding of the pathogenesis of dengue and for the future design of subunit vaccine against DENV as well.

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Author and article information

Contributors

Flávio G. da Fonseca:

ORCID: http://orcid.org/0000-0002-1416-8694

dafonseca@icb.ufmg.br

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 9 July 2020

Publication date PMC-release: 9 July 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 11302

Affiliations

[1 ]ISNI 0000 0001 2181 4888, GRID grid.8430.f, Laboratório de Virologia Básica e Aplicada, Departamento de Microbiologia, Instituto de Ciências Biológicas, , Universidade Federal de Minas Gerais, ; Belo Horizonte, MG Brazil

[2 ]ISNI 0000 0004 0635 4678, GRID grid.466576.0, Laboratório de Química de Nanoestruturas de Carbono, , Centro de Desenvolvimento da Tecnologia Nuclear-CDTN/CNEN, ; Belo Horizonte, MG Brazil

[3 ]ISNI 0000 0001 2181 4888, GRID grid.8430.f, Laboratório de Nanomateriais, Departamento de Física, , Universidade Federal de Minas Gerais, ; Belo Horizonte, MG Brazil

[4 ]ISNI 0000 0000 9688 4664, GRID grid.472872.c, Fundacao Ezequiel Dias, FUNED, ; Belo Horizonte, MG Brazil

[5 ]ISNI 0000 0004 0615 5265, GRID grid.419029.7, Laboratório de Pesquisa em Virologia, Departamento de Doenças Infecciosas e Parasitárias, , Faculdade de Medicina de São José Do Rio Preto, ; São José do Rio Preto, SP Brazil

[6 ]ISNI 0000 0001 2181 4888, GRID grid.8430.f, NanoBioMedical Research Group, Departamento de Física, , Universidade Federal de Minas Gerais, ; Belo Horizonte, MG Brazil

[7 ]ISNI 0000 0001 2181 4888, GRID grid.8430.f, Centro de Tecnologia de Vacinas, , Universidade Federal de Minas Gerais, ; Belo Horizonte, MG Brazil

[8 ]ISNI 0000 0004 0615 5265, GRID grid.419029.7, Present Address: Laboratório de Pesquisa em Virologia, Departamento de Doenças Infecciosas e Parasitárias, , Faculdade de Medicina de São José Do Rio Preto, ; São José do Rio Preto, SP Brazil

Author information

Lidia M. Andrade http://orcid.org/0000-0003-2594-4617

Edel F. Barbosa-Stancioli http://orcid.org/0000-0001-6584-4333

Mauricio L. Nogueira http://orcid.org/0000-0003-1102-2419

Flávio G. da Fonseca http://orcid.org/0000-0002-1416-8694

Article

Publisher ID: 68357

DOI: 10.1038/s41598-020-68357-9

PMC ID: 7347616

PubMed ID: 31913322

SO-VID: 5a23fcf8-f4c5-47b8-b3c8-efa19494ea19

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 November 2019

Date accepted : 22 June 2020

Funding

Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPEMIG (http://www.fapesp.br/)

Funded by: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) (https://fapemig.br/pt/); Financiadora de Inovação e Pesquisa-FINEP (http://www.finep.gov.br/)

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ScienceOpen disciplines: Uncategorized

Keywords: biosensors,infectious-disease diagnostics

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ScienceOpen disciplines: Uncategorized

Keywords: biosensors, infectious-disease diagnostics

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Nanosensors based on LSPR are able to serologically differentiate dengue from Zika infections

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Abstract

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Zika Virus

Most cited references 56

Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests.

Immune response to dengue virus and prospects for a vaccine.

Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II.

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