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Open AccessArticle
Dengue Virus Serotype 2 Intrahost Diversity in Patients with Different Clinical Outcomes
by Maria Celeste Torres 1,*OrcID,Marcos Cesar Lima de Mendonça 1,Cintia Damasceno dos Santos Rodrigues 1,Vagner Fonseca 2,3,4OrcID,Mario Sergio Ribeiro 5,Ana Paula Brandão 6,Rivaldo Venâncio da Cunha 7OrcID,Ana Isabel Dias 8,Lucy Santos Vilas Boas 8,Alvina Clara Felix 8,Maira Alves Pereira 9,Luzia Maria de Oliveira Pinto 10OrcID,Anavaj Sakuntabhai 11,†,Ana Maria Bispo de Filippis 1,† andon behalf of ZikAction Consortium 1,†
1
Laboratório de Flavivírus, Instituto Oswaldo Cruz, Fiocruz, 21040-360 Rio de Janeiro, Brazil
2
KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), School of Laboratory Medicine and Medical Sciences, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, 4041 Durban, South Africa
3
Laboratório de Genética Celular e Molecular, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, Brazil
4
Coordenação Geral dos Laboratórios de Saúde Pública/Secretaria de Vigilância em Saúde, Ministério da Saúde, (CGLAB/SVS-MS) Brasília, 70719-040 Distrito Federal, Brazil
5
Superintendência Secretaria de Vigilância em Saúde do Estado do Rio de Janeiro, 20031-142 Rio de Janeiro, Brazil
6
Laboratório Central Noel Nutels/LACEN, 20231-092 Rio de Janeiro, Brazil
7
Coordenação de Vigilância em Saúde e Laboratórios de Referência da Fundação Oswaldo Cruz, FIOCRUZ, 21040-360 Rio de Janeiro, Brazil
8
Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, 05403-000 São Paulo, Brazil
9
Fundação Ezequiel Dias/LACEN, 31630-903 Belo Horizonte, Brazil
10
Laboratório de Imunologia Viral, Instituto Oswaldo Cruz, Fiocruz, 21040-360 Rio de Janeiro, Brazil
11
Functional Genetics of Infectious Diseases, Department of Global Health, Institut Pasteur, 75015 Paris, France
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Academic Editor: Didier Musso
Viruses 2021, 13(2), 349; https://doi.org/10.3390/v13020349
Received: 27 December 2020 / Revised: 7 February 2021 / Accepted: 13 February 2021 / Published: 23 February 2021
(This article belongs to the Special Issue Endemic Arboviruses)
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Abstract
Intrahost genetic diversity is thought to facilitate arbovirus adaptation to changing environments and hosts, and it might also be linked to viral pathogenesis. Dengue virus serotype 2 (DENV-2) has circulated in Brazil since 1990 and is associated with severe disease and explosive outbreaks. Intending to shed light on the viral determinants for severe dengue pathogenesis, we sought to analyze the DENV-2 intrahost genetic diversity in 68 patient cases clinically classified as dengue fever (n = 31), dengue with warning signs (n = 19), and severe dengue (n = 18). Unlike previous DENV intrahost diversity studies whose approaches employed PCR, here we performed viral whole-genome deep sequencing from clinical samples with an amplicon-free approach, representing the real intrahost diversity scenario. Striking differences were detected in the viral population structure between the three clinical categories, which appear to be driven mainly by different infection times and selection pressures, rather than being linked with the clinical outcome itself. Diversity in the NS2B gene, however, showed to be constrained, irrespective of clinical outcome and infection time. Finally, 385 non-synonymous intrahost single-nucleotide variants located along the viral polyprotein, plus variants located in the untranslated regions, were consistently identified among the samples. Of them, 124 were exclusively or highly detected among cases with warning signs and among severe cases. However, there was no variant that by itself appeared to characterize the cases of greater severity, either due to its low intrahost frequency or the conservative effect on amino acid substitution. Although further studies are necessary to determine their real effect on viral proteins, this heightens the possibility of epistatic interactions. The present analysis represents an initial effort to correlate DENV-2 genetic diversity to its pathogenic potential and thus contribute to understanding the virus’s dynamics within its human host. | |
