MicroRNA expression profiles in patients with acute Crimean Congo hemorrhagic fever reveal possible adjustments to cellular pathways

Demir, Zekiye Cemre; Baştuğ, Aliye; Bodur, Hürrem; Ergünay, Koray; Özkul, Aykut

doi:10.1002/jmv.24667

Cited by 13 publications

(13 citation statements)

References 35 publications

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“…Through a combination of bioinformatics and gene profiling we were able to identify host pathways associated with CCHFV pathogenesis in liver cell lines. While several groups have identified genes with altered expression in CCHFV infection [43][44][45], to our knowledge this is the first time next-generation sequencing has been applied to examine the host-response in vitro to CCHFV. Our data indicates that CCHFV infection of hepatocyte cell lines induced robust antiviral and pro-inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

et al. 2020

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Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause a hemorrhagic fever in humans, with a case fatality rate of up to 40%. Cases of CCHFV have been reported in Africa, Asia, and southern Europe; and recently, due to the expanding range of its vector, autochthonous cases have been reported in Spain. Although it was discovered over 70 years ago, our understanding of the pathogenesis of this virus remains limited. We used RNA-Seq in two human liver cell lines (HepG2 and Huh7) infected with CCHFV (strain IbAr10200), to examine kinetic changes in host expression and viral replication simultaneously at 1 and 3 days post infection. Through this, numerous host pathways were identified that were modulated by the virus including: antiviral response and endothelial cell leakage. Notably, the genes encoding DDX60, a cytosolic component of the RIG-I signalling pathway and OAS2 were both shown to be dysregulated. Interestingly, PTPRR was induced in Huh7 cells but not HepG2 cells. This has been associated with the TLR9 signalling cascade, and polymorphisms in TLR9 have been associated with poor outcomes in patients. Additionally, we performed whole-genome sequencing on CCHFV to assess viral diversity over time, and its relationship to the host response. As a result, we have demonstrated that through next-generation mRNA deep-sequencing it is possible to not only examine mRNA gene expression, but also to examine viral quasispecies and typing of the infecting strain.

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Section: Discussionmentioning

confidence: 99%

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

et al. 2020

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“…Preliminary analysis showed that the expression of microRNAs related to regulation of cytokine expression is altered in CCHF patients (Demir et al, 2017). Genetic factors and immune status of the host, as well as genetic differences in CCHFV strains, may play a significant role in the virus-host interface, however, there are no studies available.…”

Section: Host-pathogen Interactionsmentioning

confidence: 99%

Crimean-Congo Hemorrhagic Fever: Tick-Host-Virus Interactions

Papa

Tsergouli

Tsioka

et al. 2017

Front. Cell. Infect. Microbiol.

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Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted to humans by bite of infected ticks or by direct contact with blood or tissues of viremic patients or animals. It causes to humans a severe disease with fatality up to 30%. The current knowledge about the vector-host-CCHFV interactions is very limited due to the high-level containment required for CCHFV studies. Among ticks, Hyalomma spp. are considered the most competent virus vectors. CCHFV evades the tick immune response, and following its replication in the lining of the tick's midgut, it is disseminated by the hemolymph in the salivary glands and reproductive organs. The introduction of salivary gland secretions into the host cells is the major route via which CCHFV enters the host. Following an initial amplification at the site of inoculation, the virus is spread to the target organs. Apoptosis is induced via both intrinsic and extrinsic pathways. Genetic factors and immune status of the host may affect the release of cytokines which play a major role in disease progression and outcome. It is expected that the use of new technology of metabolomics, transcriptomics and proteomics will lead to improved understanding of CCHFV-host interactions and identify potential targets for blocking the CCHFV transmission.

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“…Increased expression of SPRED1 was suggested to be one of the mechanisms that augment endothelial cells permeability, leading to HPS. A recent study with PBMC of patients presenting acute hemorrhagic fever caused by the Crimean-Congo Hemorrhagic Fever Virus (CCHFV) showed the deregulation of several miRNAs, some of them associated with innate immunity and viral escape mechanisms [ 48 ]. The only study with phleboviruses described the association between miR-142-3p and the endocytic vesicle protein VAMP3, suggesting a control mechanism for the intracellular trafficking of Uukuniemi Virus (UUKV) [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection

et al. 2018

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Oropouche Virus is the etiological agent of an arbovirus febrile disease that affects thousands of people and is widespread throughout Central and South American countries. Although isolated in 1950’s, still there is scarce information regarding the virus biology and its prevalence is likely underestimated. In order to identify and elucidate interactions with host cells factors and increase the understanding about the Oropouche Virus biology, we performed microRNA (miRNA) and target genes screening in human hepatocarcinoma cell line HuH-7. Cellular miRNAs are short non-coding RNAs that regulates gene expression post-transcriptionally and play key roles in several steps of viral infections. The large scale RT-qPCR based screening found 13 differentially expressed miRNAs in Oropouche infected cells. Further validation confirmed that miR-217 and miR-576-3p were 5.5 fold up-regulated at early stages of virus infection (6 hours post-infection). Using bioinformatics and pathway enrichment analysis, we predicted the cellular targets genes for miR-217 and miR-576-3p. Differential expression analysis of RNA from 95 selected targets revealed genes involved in innate immunity modulation, viral release and neurological disorder outcomes. Further analysis revealed the gene of decapping protein 2 (DCP2), a previous known restriction factor for bunyaviruses transcription, as a miR-217 candidate target that is progressively down-regulated during Oropouche infection. Our analysis also showed that activators genes involved in innate immune response through IFN-β pathway, as STING (Stimulator of Interferon Genes) and TRAF3 (TNF-Receptor Associated Factor 3), were down-regulated as the infection progress. Inhibition of miR-217 or miR-576-3p restricts OROV replication, decreasing viral RNA (up to 8.3 fold) and virus titer (3 fold). Finally, we showed that virus escape IFN-β mediated immune response increasing the levels of cellular miR-576-3p resulting in a decreasing of its partners STING and TRAF3. We concluded stating that the present study, the first for a Peribunyaviridae member, gives insights in its prospective pathways that could help to understand virus biology, interactions with host cells and pathogenesis, suggesting that the virus escapes the antiviral cellular pathways increasing the expression of cognates miRNAs.

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MicroRNA expression profiles in patients with acute Crimean Congo hemorrhagic fever reveal possible adjustments to cellular pathways

Cited by 13 publications

References 35 publications

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus

Crimean-Congo Hemorrhagic Fever: Tick-Host-Virus Interactions

MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection

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