Dataset Information

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.

ABSTRACT: Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.

SUBMITTER: Shah PS

PROVIDER: S-EPMC6474419 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.

Shah Priya S PS Link Nichole N Jang Gwendolyn M GM Sharp Phillip P PP Zhu Tongtong T Swaney Danielle L DL Johnson Jeffrey R JR Von Dollen John J Ramage Holly R HR Satkamp Laura L Newton Billy B Hüttenhain Ruth R Petit Marine J MJ Baum Tierney T Everitt Amanda A Laufman Orly O Tassetto Michel M Shales Michael M Stevenson Erica E Iglesias Gabriel N GN Shokat Leila L Tripathi Shashank S Balasubramaniam Vinod V Webb Laurence G LG Aguirre Sebastian S Willsey A Jeremy AJ Garcia-Sastre Adolfo A Pollard Katherine S KS Cherry Sara S Gamarnik Andrea V AV Marazzi Ivan I Taunton Jack J Fernandez-Sesma Ana A Bellen Hugo J HJ Andino Raul R Krogan Nevan J NJ

Cell 20181201 7

Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host P ...[more]

PMID: 30550790

Similar Datasets

Project description:The 2015/2016 Zika virus epidemic in South and Central America left the scientific community urgently trying to understand the factors that contribute to Zika virus pathogenesis. Because multiple other flaviviruses are endemic in areas where Zika virus emerged, it is hypothesized that a key to understanding Zika virus disease severity is to study Zika virus infection in the context of prior flavivirus exposure. Human and animal studies have highlighted the idea that having been previously exposed to a different flavivirus may modulate the immune response to Zika virus. However, it is still unclear how prior flavivirus exposure impacts Zika viral burden and disease. In this murine study, we longitudinally examine multiple factors involved in Zika disease, linking viral burden with increased neurological disease severity, weight loss, and inflammation. We show that prior heterologous flavivirus exposure with dengue virus type 2 or 3 or the vaccine strain of yellow fever provides protection from mortality in a lethal Zika virus challenge. However, reduction in viral burden and Zika disease varies depending on the infecting primary flavivirus; with primary Zika virus infection being most protective from Zika virus challenge, followed by dengue virus 2, with yellow fever and dengue virus 3 protecting against mortality but showing more severe disease. This study demonstrates the variation in protective effects of prior flavivirus exposure on Zika virus pathogenesis and identifies distinct relationships between primary flavivirus infection and the potential for Zika virus disease. IMPORTANCE The emergence and reemergence of various vector-borne diseases in recent years highlights the need to understand the mechanisms of protection for each pathogen. In this study, we investigated the impact of prior exposure to Zika virus, dengue virus serotypes 2 or 3, or the vaccine strain of yellow fever on pathogenesis and disease outcomes in a mouse model of Zika virus infection. We found that prior exposure to a heterologous flavivirus was protective from mortality, and to varying degrees, prior flavivirus exposure was protective against neurological disease, weight loss, and severe viral burden during a lethal Zika challenge. Using a longitudinal and cross-sectional study design, we were able to link multiple disease parameters, including viral burden, with neurological disease severity, weight loss, and inflammatory response in the context of flavivirus infection. This study demonstrates a measurable but varied impact of prior flavivirus exposure in modulating flavivirus pathophysiology. Given the cyclic nature of most flavivirus outbreaks, this work will contribute to the forecasting of disease severity for future outbreaks.

Dataset Information

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.

Publications

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets