Genome-wide search for differentially expressed RNAs responsible for the effects induced by Ebola virus replication and transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE105414 | GEO | 2018/02/14
REPOSITORIES: GEO
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Project description:Ebola virus (EBOV) causes epidemics with high mortality, yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, providing insight into pathogenesis: e.g., immature, proliferative monocyte-lineage cells with reduced antigen presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV down-regulates STAT1 mRNA and interferon signaling, and up-regulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response, and provides a framework for characterizing host-virus interactions under maximum containment.
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Project description:Understanding the molecular interactions of host cells with Ebola virus (EBOV) is integral for further therapeutic development of antivirals. We performed a proximity-dependent protein interaction screen for six of seven EBOV proteins to characterize the EBOV-host interactome. Using network analysis, putative EBOV interacting proteins were mapped to a human protein interactome. We overlayed viral protein interactions onto the host network. Within this map, several known EBOV-host protein interactions were identified, as well as several cell processes, such as RNA processing, previously implicated in EBOV replication. Furthermore, this interactome revealed novel interactions between EBOV proteins and host proteins arranged in functional complexes. As proof of this concept, we characterized the interaction between EBOV VP35 and the mRNA decapping complex, which regulates mRNA turnover in host cells. Our protein-protein interaction data demonstrate that VP35 engages multiple components of this complex by binding binds the scaffold protein EDC4. Inhibiting expression of mRNA decapping complex components EDC4, EDC3, or DCP2 inhibited viral replication by reducing early viral RNA synthesis. Our approach examining EBOV-host protein interactions in conjunction with network analysis reveals how EBOV interacts with entire cellular machines as opposed to singular cell proteins to promote its replication.
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