Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors

Selinger, Martin; Vechtova, Pavlina; Tykalová, Hana; Ošlejšková, Petra; Rumlová, Michaela; Štěrba, Ján; Grubhoffer, Libor

doi:10.1016/j.csbj.2022.05.052

Cited by 21 publications

(17 citation statements)

References 76 publications

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“…Candidate genes were narrowed down by cis-eQTL analysis including Cand1 , Tbc1d30, and Rassf3 in tissues relevant to cancer. TBC1 domain family member 30 ( Tbc1d30 61,62 and Glucosamine (N-Acetyl)-6-Sulfatase (Gns 63 ) are of particular interest due to missense and splice variants, respectively, that are precited to impact protein function.…”

Section: Discussionmentioning

confidence: 99%

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Simon,

Simmons,

Kim

et al. 2024

Preprint

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Breast cancer (BC) is the most common cancer and the second cause of death in US women. Our lack of understanding of how genetic variants affect molecular mechanisms that mediate BC aggression poses a substantial obstacle to advancements in cancer diagnosis and therapy. To examine genetic variants on BC traits, a novel murine model was created with robust phenotypic and genomic variation. The FVB C3(1)-T-antigen (C3Tag) mouse develops spontaneous tumors in the mammary glands of female mice with a mean latency of 4-5 months of age. This genetically engineered mouse model (GEMM) is well established to resemble human basal-like TNBC. TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family - the largest and best characterized genetic reference population. The new model is termed BXD-BC and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. We hypothesized that examination of BXD-BC GEMMs will enable the identification of susceptibility loci, candidate genes, and molecular networks that underlie variation of multiple BC phenotypes. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. Interestingly, 2 BXD-BC strains never developed tumors out to 1 year of age. Thus, BXD-BC strains demonstrate variance in cancer susceptibility and progression compared to the parent C3Tag GEMM, indicating the presence of genetic modifiers. Through an unbiased systematic quantification of breast cancer severity across BXD-BC hybrids, we identified several significant quantitative trait loci (QTL) and candidate genes for specific tumor traits. In combination with public human GWAS datasets, we defined syntenic regions, candidate genes, and underlying networks through cross-species systems genetics analyses to demonstrate the translational validity of conserved, biologically relevant, and targetable candidates. Our findings suggest conserved candidates predicting TNBC patient survival. In sum, the BXD-BC resource is an innovative, reliable, and robust preclinical model that reflects robust genetic heterogeneity. Using cutting-edge systems genetics, we have identified genetic modifiers of BC phenotypic variation that could be targeted to advance therapeutic limitations or as biomarkers of risk or response to therapy.

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Section: Discussionmentioning

confidence: 99%

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Simon,

Simmons,

Kim

et al. 2024

Preprint

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“…Despite this, and perhaps in part because of it, there are still considerable gaps in our understanding of TBE neuroinvasion. The progress in this area in recent years has been incremental, although is leading to a considerable body of data now that ‘omics’ technologies are being applied to the infection process [32 ▪▪ ]. Similarly, developments in therapies for TBE once encephalitis has been diagnosed have identified the RdRp protein of the virus as a key target, but further progress is needed to show efficacy in experimental models to propel them towards treatment of patients.…”

Section: Discussionmentioning

confidence: 99%

“…Infection of nonneuronal cells has been documented but it is unclear how this contributes to the pathology of TBEV infection. A comprehensive transcriptomic analysis has shown that the Hypr strain causes cell death in neurons but not astrocytes and that this is underpinned by cellular and host modulation of the transcriptional response to infection [32 ▪▪ ]. There was a marked increase in microRNAs within astrocyte cells compared with neuronal counterparts, although it remains unclear whether this is an active response of the cell to control virus or, conversely, the virus modulating the cellular environment to promote virion replication.…”

Section: Pathogenesismentioning

confidence: 99%

Tick-borne encephalitis

Johnson

Migné

Gonzalez

2023

Current Opinion in Infectious Diseases

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Purpose of reviewTick-borne encephalitis continues to be one of the most significant causes of viral encephalitis in Europe and Asia. This review will focus on recent developments in the epidemiology, pathogenesis and therapeutic approaches related to infection with tick-borne encephalitis virus. Recent findingsThere is a growing consensus that tick-borne encephalitis viruses are increasing in geographical range, with countries previously free of disease reporting detection of both human cases and presence of virus within indigenous tick populations. The drivers for this are multifactorial but underpinned by humanmediated climate change. Recent developments in pathogenesis have focussed on the intracellular response to infection, particularly in different cell types within the central nervous system (CNS) that are revealing the array of cellular networks triggered by infection. This in turn highlights the need for small molecule therapeutics, such as nucleoside analogues, that can enter the CNS, and the intracellular environment, to inhibit virus replication following neuroinvasion.

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“…HSPA6 is a strictly stress-inducible member of Hsp70 family and has low or nondetectable expression levels in most cells [ 27 ]. However, it has been found to be expressed in response to cellular stresses including viral infection, such as tick-borne encephalitis virus [ 28 ] and Enterovirus 71 [ 29 ]. HSPA6 was also shown to be expressed at high levels in neurodegenerative diseases and in tissue or cells under oxidative stress [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression

Chi¹,

Shan²,

Cui³

2022

Analytical Cellular Pathology

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Objective. Respiratory syncytial virus (RSV) infection is an important cause of hospitalization of children worldwide, leading to significant morbidity and mortality. RSV infection leads to increasing inflammatory and apoptosis events in the airway epithelium through mechanisms involving ROS generation. The antioxidant N-acetyl-L-cysteine (NAC) has been shown to inhibit influenza virus replication and to reduce the secretion of inflammatory and apoptotic mediators during virus infection. The study aims to investigate the effects of NAC on human bronchial epithelial cells BEAS-2B and HSPA6 expression during RSV infection. Methods. CCK-8 assays were performed to evaluate cell survival. The production of proinflammatory factors, TNF-α, IL-6, IL-1β, IL-18, and MUC5AC was examined by quantitative real-time PCR and ELISA. Oxidative stress was determined by reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)/glutathione disulfide (GSSG) ratio. Immunoblotting analysis of epidermal growth factor receptor (EGFR) and its phosphorylation was performed. The antiviral effect of NAC was assessed by determining viral titers using plaque assay. Results. RSV infection reduced cell survival, promoted the release of proinflammatory factors, increased the ROS production and MDA concentration, and diminished the SOD activity and GSH/GSSG ratio, all which were attenuated by NAC treatment. Accordingly, NAC treatment inhibited the activation of EGFR and MUC5AC in BEAS-2B cells with RSV infection. Furthermore, NAC administration resulted in a marked decrease in RSV-induced HSPA6 expression in BEAS-2B cells. Concomitantly, EPB treatment led to an evident inhibition of RSV fusion gene and viral replication in RSV-infected BEAS-2B cells. Conclusion. This work supports the use of NAC to exert antimucin synthesis, anti-inflammatory, antioxidant, and antiviral effects on airway epithelium during RSV infection.

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Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors

Cited by 21 publications

References 76 publications

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Determining susceptibility loci in triple negative breast cancer using a novel pre-clinical model

Tick-borne encephalitis

N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression

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