Single point mutations in the helicase domain of the NS3 protein enhance dengue virus replicative capacity in human monocyte-derived dendritic cells and circumvent the type I interferon response
| Autor: | C N Duarte dos Santos, Nilson Ivo Tonin Zanchin, Daniel S. Mansur, L de Borba, Daisy Maria Strottmann, Juliano Bordignon, Guilherme Ferreira Silveira |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Immunology Dengue Vaccines Biology Dengue virus medicine.disease_cause Virus Replication DENDRITIC CELLS Virus Monocytes Ciencias Biológicas Dengue 03 medical and health sciences Interferon medicine Immunology and Allergy Humans Point Mutation DENGUE VIRUS VIRAL REPLICATIVE CAPACITY Dengue vaccine Cells Cultured Immune Evasion Adenosine Triphosphatases NS3 Point mutation Serine Endopeptidases TYPE I IFN Dendritic Cells Original Articles Bioquímica y Biología Molecular Dengue Virus Microarray Analysis Virology 030104 developmental biology Viral replication Interferon Type I NS3 HELICASE CIENCIAS NATURALES Y EXACTAS Interferon type I medicine.drug |
| Zdroj: | Clinical and experimental immunology. 183(1) |
| ISSN: | 1365-2249 |
| Popis: | Dengue is the most prevalent arboviral disease worldwide. The outcome of the infection is determined by the interplay of viral and host factors. In the present study, we evaluated the cellular response of human monocyte-derived DCs (mdDCs) infected with recombinant dengue virus type 1 (DV1) strains carrying a single point mutation in the NS3hel protein (L435S or L480S). Both mutated viruses infect and replicate more efficiently and produce more viral progeny in infected mdDCs compared with the parental, non-mutated virus (vBACDV1). Additionally, global gene expression analysis using cDNA microarrays revealed that the mutated DVs induce the up-regulation of the interferon (IFN) signalling and pattern recognition receptor (PRR) canonical pathways in mdDCs. Pronounced production of type I IFN were detected specifically in mdDCs infected with DV1-NS3hel-mutated virus compared with mdDCs infected with the parental virus. In addition, we showed that the type I IFN produced by mdDCs is able to reduce DV1 infection rates, suggesting that cytokine function is effective but not sufficient to mediate viral clearance of DV1-NS3hel-mutated strains. Our results demonstrate that single point mutations in subdomain 2 have important implications for adenosine triphosphatase (ATPase) activity of DV1-NS3hel. Although a direct functional connection between the increased ATPase activity and viral replication still requires further studies, these mutations speed up viral RNA replication and are sufficient to enhance viral replicative capacity in human primary cell infection and circumvent type I IFN activity. This information may have particular relevance for attenuated vaccine protocols designed for DV. Fil: Silveira, G. F.. Instituto Carlos Chagas; Brasil Fil: Strottmann, D. M.. Instituto Carlos Chagas; Brasil Fil: de Borba, Luana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Instituto Carlos Chagas; Brasil Fil: Mansur, D. S.. Universidade Federal Da Santa Catarina; Brasil Fil: Zanchin, N. I. T.. Instituto Carlos Chagas; Brasil Fil: Bordignon, J.. Instituto Carlos Chagas; Brasil Fil: Duarte dos Santos, C.N.. Instituto Carlos Chagas; Brasil |
| Databáze: | OpenAIRE |
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