Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells

Hölzer, Martin; Krähling, Verena; Amman, Fabian; Barth, Emanuel; Bernhart, Stephan H.; Carmelo, Victor Adriano Okstoft; Collatz, Maximilian; Doose, Gero; Eggenhofer, Florian; Ewald, Jan; Fallmann, Jörg; Feldhahn, Lasse; Fricke, Markus; Gebauer, Juliane; Gruber, Andreas J.; Hufsky, Franziska; Indrischek, Henrike; Kanton, Sabina; Linde, Jörg; Mostajo, Nelly; Ochsenreiter, Roman; Riege, Konstantin; Rivarola-Duarte, Lorena; Sahyoun, Abdullah H.; Saunders, Sita J.; Seemann, Stefan E.; Tanzer, Andrea; Vogel, Bertram; Wehner, Stefanie; Wolfinger, Michael T.; Backofen, Rolf; Gorodkin, Jan; Große, Ivo; Hofacker, Ivo L.; Hoffmann, Steve; Kaleta, Christoph; Stadler, Peter F.; Becker, Stephan; Marz, Manja

doi:10.1038/srep34589

Cited by 47 publications

(60 citation statements)

References 99 publications

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“…A recently published study reported no significant changes in expression of host genes and in induction of pathways relevant for viral infections in R06EJ cells infected with EBOV or MARV (52). However, our study did show induction of multiple genes.…”

Section: Discussioncontrasting

confidence: 79%

Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Kuzmin

Schwarz

Ilinykh

et al. 2017

J Virol

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Marburg (MARV) and Ebola (EBOV) viruses are zoonotic pathogens that cause severe hemorrhagic fever in humans. The natural reservoir of MARV is the Egyptian rousette bat (Rousettus aegyptiacus); that of EBOV is unknown but believed to be another bat species. The Egyptian rousette develops subclinical productive infection with MARV but is refractory to EBOV. Interaction of filoviruses with hosts is greatly affected by the viral interferon (IFN)-inhibiting domains (IID). Our study was aimed at characterization of innate immune responses to filoviruses and the role of filovirus IID in bat and human cells. The study demonstrated that EBOV and MARV replicate to similar levels in all tested cell lines, indicating that permissiveness for EBOV at cell and organism levels do not necessarily correlate. Filoviruses, particularly MARV, induced a potent innate immune response in rousette cells, which was generally stronger than that in human cells. Both EBOV VP35 and VP24 IID were found to suppress the innate immune response in rousette cells, but only VP35 IID appeared to promote virus replication. Along with IFN-␣ and IFN-␤, IFN-␥ was demonstrated to control filovirus infection in bat cells but not in human cells, suggesting host species specificity of the antiviral effect. The antiviral effects of bat IFNs appeared not to correlate with induction of IFN-stimulated genes 54 and 56, which were detected in human cells ectopically expressing bat IFN-␣ and IFN-␤. As bat IFN-␥ induced the type I IFN pathway, its antiviral effect is likely to be partially induced via cross talk.IMPORTANCE Bats serve as reservoirs for multiple emerging viruses, including filoviruses, henipaviruses, lyssaviruses, and zoonotic coronaviruses. Although there is no evidence for symptomatic disease caused by either Marburg or Ebola viruses in bats, spillover of these viruses into human populations causes deadly outbreaks. The reason for the lack of symptomatic disease in bats infected with filoviruses remains unknown. The outcome of a virus-host interaction depends on the ability of the host immune system to suppress viral replication and the ability of a virus to counteract the host defenses. Our study is a comparative analysis of the host innate immune response to either MARV or EBOV infection in bat and human cells and the role of viral interferon-inhibiting domains in the host innate immune responses. The data are useful for understanding the interactions of filoviruses with natural and accidental hosts and for identification of factors that influence filovirus evolution.

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Section: Discussioncontrasting

confidence: 79%

Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Kuzmin

Schwarz

Ilinykh

et al. 2017

J Virol

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“…Indeed, both FOS and JUN are targets themselves for the AP1 transcription factor and therefore would be expected to further promote the AP1 response as the infection progressed. It is important to acknowledge that other studies have also reported the upregulation of both JUN (39,43) and FOS (20,39) in human Huh7 cells infected with EBOV. The increased expression and activity of AP1 have also been reported in human cells infected with other viruses, including influenza virus (44), herpesvirus (45), and hepatitis C virus (46).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that both JUN and FOS mRNAs are upregulated in human Huh7 cells following EBOV infection (39). A549, HeLa, and HEK293T cells were infected with EBOV (MOI ϭ 5) as described above for cells of the other cell lines.…”

Section: Resultsmentioning

confidence: 99%

Comparative Transcriptomics Highlights the Role of the Activator Protein 1 Transcription Factor in the Host Response to Ebolavirus

Wynne

Todd

Boyd

et al. 2017

J Virol

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Ebolavirus and Marburgvirus comprise two genera of negative-sense singlestranded RNA viruses that cause severe hemorrhagic fevers in humans. Despite considerable research efforts, the molecular events following Ebola virus (EBOV) infection are poorly understood. With the view of identifying host factors that underpin EBOV pathogenesis, we compared the transcriptomes of EBOV-infected human, pig, and bat kidney cells using a transcriptome sequencing (RNA-seq) approach. Despite a significant difference in viral transcription/replication between the cell lines, all cells responded to EBOV infection through a robust induction of extracellular growth factors. Furthermore, a significant upregulation of activator protein 1 (AP1) transcription factor complex members FOS and JUN was observed in permissive cell lines. Functional studies focusing on human cells showed that EBOV infection induces protein expression, phosphorylation, and nuclear accumulation of JUN and, to a lesser degree, FOS. Using a luciferase-based reporter, we show that EBOV infection induces AP1 transactivation activity within human cells at 48 and 72 h postinfection. Finally, we show that JUN knockdown decreases the expression of EBOV-induced host gene expression. Taken together, our study highlights the role of AP1 in promoting the host gene expression profile that defines EBOV pathogenesis. IMPORTANCE Many questions remain about the molecular events that underpin filovirus pathophysiology. The rational design of new intervention strategies, such as postexposure therapeutics, will be significantly enhanced through an in-depth understanding of these molecular events. We believe that new insights into the molecular pathogenesis of EBOV may be possible by examining the transcriptomic response of taxonomically diverse cell lines (derived from human, pig, and bat). We first identified the responsive pathways using an RNA-seq-based transcriptomics approach. Further functional and computational analysis focusing on human cells highlighted an important role for the AP1 transcription factor in mediating the transcriptional response to EBOV infection. Our study sheds new light on how host transcription factors respond to and promote the transcriptional landscape that follows viral infection.

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“…Possibly, the solution to better understand and fight these pathogens lies in the uniquely developed immune system of bats. 15,16 . Studying bats and their genomes is likely to have high impacts on various scientific fields, including healthy ageing, immune and ecosystem functioning, the evolution of sensory perception and human communication, and mammalian genome architecture (see the recent Bat1K review for further details 2 ).…”

Section: Figurementioning

confidence: 99%

A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes

Berrospi

Lataretu

Krautwurst

et al. 2019

Preprint

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Although bats are increasingly becoming the focus of scientific studies due to their unique properties, these exceptional animals are still among the least studied mammals. Assembly quality and completeness of bat genomes vary a lot and especially non-coding RNA (ncRNA) annotations are incomplete or simply missing. Accordingly, standard bioinformatics pipelines for gene expression analysis often ignore ncRNAs such as microRNAs or long antisense RNAs. The main cause of this problem is the use of incomplete genome annotations. We present a complete screening for ncRNAs within 16 bat genomes. NcRNAs affect a remarkable variety of vital biological functions, including gene expression regulation, RNA processing, RNA interference and, as recently described, regulatory processes in viral infections. Within all investigated bat assemblies we annotated 667 ncRNA families including 162 snoRNAs and 193 miRNAs as well as rRNAs, tRNAs, several snRNAs and lncRNAs, and other structural ncRNA elements. We validated our ncRNA candidates by six RNA-Seq data sets and show significant expression patterns that have never been described before in a bat species on such a large scale. Our annotations will be usable as a resource (Electronic Supplement) for deeper studying of bat evolution, ncRNAs repertoire, gene expression and regulation, ecology, and important host-virus interactions.Supplementary information: is available at rna.uni-jena.de/supplements/bats, the Open Science Framework (doi.org/10.17605/OSF.IO/4CMDN), and GitHub (github.com/rnajena/bats_ncrna).

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Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells

Cited by 47 publications

References 99 publications

Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Innate Immune Responses of Bat and Human Cells to Filoviruses: Commonalities and Distinctions

Comparative Transcriptomics Highlights the Role of the Activator Protein 1 Transcription Factor in the Host Response to Ebolavirus

A comprehensive annotation and differential expression analysis of short and long non-coding RNAs in 16 bat genomes

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