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Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity.

ABSTRACT: Dengue and Zika viruses cocirculate annually in endemic areas of Mexico, causing outbreaks of different magnitude and severity every year, suggesting a continuous selection of Flavivirus variants with variable phenotypes of transmissibility and virulence. To evaluate if Flavivirus variants with different phenotypes cocirculate during outbreaks, we isolated dengue and Zika viruses from blood samples of febrile patients from Oaxaca City during the 2016 and 2019 epidemic years. We compared their replication kinetics in human cells, susceptibility to type I interferon antiviral response, and the accumulation of subgenomic RNA on infected cells. We observed correlations between type I interferon susceptibility and subgenomic RNA accumulation, with high hematocrit percentage and thrombocytopenia. Our results suggest that Flaviviruses that cocirculate in Oaxaca, Mexico, have variable sensitivity to the antiviral activity of type I interferons, and this phenotypic trait correlates with the severity of the disease.

SUBMITTER: Castro-Jimenez TK

PROVIDER: S-EPMC9254156 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity.

Castro-Jiménez Tannya Karen TK Gómez-Legorreta Laura Cristina LC López-Campa Laura Alejandra LA Martínez-Torres Valeria V Alvarado-Silva Marcos M Posadas-Mondragón Araceli A Díaz-Lima Nallely N Angulo-Mendez Hilda Arcelia HA Mejía-Domínguez Nancy R NR Vaca-Paniagua Felipe F Ávila-Moreno Federico F García-Cordero Julio J Cedillo-Barrón Leticia L Aguilar-Ruíz Sergio Roberto SR Bustos-Arriaga José J

Frontiers in cellular and infection microbiology 20220621

Dengue and Zika viruses cocirculate annually in endemic areas of Mexico, causing outbreaks of different magnitude and severity every year, suggesting a continuous selection of <i>Flavivirus</i> variants with variable phenotypes of transmissibility and virulence. To evaluate if <i>Flavivirus</i> variants with different phenotypes cocirculate during outbreaks, we isolated dengue and Zika viruses from blood samples of febrile patients from Oaxaca City during the 2016 and 2019 epidemic years. We com ...[more]

PMID: 35800385

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Project description:BackgroundDengue (DEN) is a serious cause of mortality and morbidity in the world including Mexico, where the infection is endemic. One of the states with the highest rate of dengue cases is Oaxaca. The cause of DEN is a positive-sense RNA virus, the dengue virus (DENV) that evolves rapidly increasing its variability due to the absence of a repair mechanism that leads to approximately one mutational event per genome replication; which results in enhancement of viral adaptation, including the escape from host immune responses. Additionally, recombination may play a role in driving the evolution of DENV, which may potentially affect virulence and cause host tropism changes. Recombination in DENV has not been described in Mexican strains, neither has been described the relevance in virus evolution in an endemic state such as Oaxaca where the four serotypes of DENV are circulating.ResultsTo study whether there are isolates from Oaxaca having recombination, we obtained the sequence of 6 different isolates of DENV-2 Asian/American genotype from the outbreak 2005-6, one clone of the C(91)-prM-E-NS1(2400) structural genes, and 10 clones of the E gene from the isolate MEX_OAX_1656_05. Evidence of recombination was found by using different methods along with two softwares: RDP3 and GARD. The Oaxaca MEX_OAX_1656_05 and MEX_OAX_1038_05 isolates sequenced in this study were recombinant viruses that incorporate the genome sequence from the Cosmopolitan genotype. Furthermore, the clone of the E gene namely MEX_OAX_165607_05 from this study was also recombinant, incorporating genome sequence from the American genotype.ConclusionsThis is the first report of recombination in DENV-2 in Mexico. Given such a recombinant activity new genomic combinations were produced, this could play a significant role in the DENV evolution and must be considered as a potentially important mechanism generating genetic variation in this virus with serious implications for the vaccines and drugs formulation as occurs for other viruses like poliovirus, influenza and HIV.

Project description:BackgroundDengue (DEN) is an infectious disease caused by the DEN virus (DENV), which belongs to the Flavivirus genus in the family Flaviviridae. It has a (+) sense RNA genome and is mainly transmitted to humans by the vector mosquito Aedes aegypti. Dengue fever (DF) and dengue hemorrhagic fever (DHF) are caused by one of four closely related virus serotypes (DENV-1, DENV-2, DENV-3 and DENV-4). Epidemiological and evolutionary studies have indicated that host and viral factors are involved in determining disease outcome and have proved the importance of viral genotype in causing severe epidemics. Host immune status and mosquito vectorial capacity are also important influences on the severity of infection. Therefore, an understanding of the relationship between virus variants with altered amino acids and high pathogenicity will provide more information on the molecular epidemiology of DEN. Accordingly, knowledge of the DENV serotypes and genotypes circulating in the latest DEN outbreaks around the world, including Mexico, will contribute to understanding DEN infections.Results1. We obtained 88 isolates of DENV, 27 from Oaxaca and 61 from Veracruz. 2. Of these 88 isolates, 16 were serotype 1; 62 serotype 2; 7 serotype 3; and 2 serotype 4. One isolate had 2 serotypes (DENV-2 and -1). 3. Partial nucleotide sequences of the genes encoding C- prM (14 sequences), the NS3 helicase domain (7 sequences), the NS5 S-adenosyl methionine transferase domain (7 sequences) and the RNA-dependent RNA polymerase (RdRp) domain (18 sequences) were obtained. Phylogenetic analysis showed that DENV-2 isolates belonged to the Asian/American genotype. In addition, the Asian/American genotype was divided into two clusters, one containing the isolates from 2001 and the other the isolates from 2005-2006 with high bootstrap support of 94%.ConclusionDENV-2 was the predominant serotype in the DF and DHF outbreak from 2005 to 2006 in Oaxaca State as well as in the 2006 outbreak in Veracruz State, with the Asian/American genotype prevalent in both states. Interestingly, DENV-1 and DENV-2 were the only serotypes related to DHF cases. In contrast, DENV-3 and DENV-4 were poorly represented according to epidemiological data reported in Mexico. We found that isoleucine was replaced by valine at residue 106 of protein C in the isolates from these 2005-2006 outbreaks and in those from the 1997, 1998 and 2001 outbreaks in the Caribbean islands. We suggested that this amino acid change may be used as a signature for isolates arising in the Caribbean islands and pertaining to the Asian/American genotype. Other amino acid changes are specific for the Asian/American, Asian and American strains.

Dataset Information

Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity.

Publications

Variability in Susceptibility to Type I Interferon Response and Subgenomic RNA Accumulation Between Clinical Isolates of Dengue and Zika Virus From Oaxaca Mexico Correlate With Replication Efficiency in Human Cells and Disease Severity.

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