scholarly journals From Plant Survival Under Severe Stress to Anti-Viral Human Defense – A Perspective That Calls for Common Efforts

2021 ◽  
Vol 12 ◽  
Author(s):  
Birgit Arnholdt-Schmitt ◽  
Gunasekaran Mohanapriya ◽  
Revuru Bharadwaj ◽  
Carlos Noceda ◽  
Elisete Santos Macedo ◽  
...  
Keyword(s):  
Target Genes ◽  
De Novo ◽  
Complex Trait ◽  
Transcript Level ◽  
Severe Stress ◽  
Human Virus ◽  
Defense Strategies ◽  
Infected Cells ◽  
Strategy Design

Reprogramming of primary virus-infected cells is the critical step that turns viral attacks harmful to humans by initiating super-spreading at cell, organism and population levels. To develop early anti-viral therapies and proactive administration, it is important to understand the very first steps of this process. Plant somatic embryogenesis (SE) is the earliest and most studied model for de novo programming upon severe stress that, in contrast to virus attacks, promotes individual cell and organism survival. We argued that transcript level profiles of target genes established from in vitro SE induction as reference compared to virus-induced profiles can identify differential virus traits that link to harmful reprogramming. To validate this hypothesis, we selected a standard set of genes named ‘ReprogVirus’. This approach was recently applied and published. It resulted in identifying ‘CoV-MAC-TED’, a complex trait that is promising to support combating SARS-CoV-2-induced cell reprogramming in primary infected nose and mouth cells. In this perspective, we aim to explain the rationale of our scientific approach. We are highlighting relevant background knowledge on SE, emphasize the role of alternative oxidase in plant reprogramming and resilience as a learning tool for designing human virus-defense strategies and, present the list of selected genes. As an outlook, we announce wider data collection in a ‘ReprogVirus Platform’ to support anti-viral strategy design through common efforts.

scholarly journals ROS/RNS balancing, aerobic fermentation regulation and cell cycle control a complex early trait ('CoV-MAC-TED') for combating SARS-CoV-2-induced cell reprogramming

2021 ◽  
Author(s):  
Jose Helio Costa ◽  
Gunasekharan Mohanapriya ◽  
Bharadwaj Revuru ◽  
Carlos Noceda ◽  
Karine Leitao Lima Thiers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
De Novo ◽  
Cell Cycle Control ◽  
Redox Homeostasis ◽  
Complex Trait ◽  
Transcript Level ◽  
Aerobic Fermentation ◽  
General Observation

In a perspective entitled From plant survival under severe stress to anti-viral human defense we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named ReprogVirus was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the ReprogVirus platform was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to RegroVirus complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called CoV-MAC-TED. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target CoV-MAC-TED in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that de-stressing disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.

scholarly journals ROS/RNS Balancing, Aerobic Fermentation Regulation and Cell Cycle Control – a Complex Early Trait (‘CoV-MAC-TED’) for Combating SARS-CoV-2-Induced Cell Reprogramming

2021 ◽  
Vol 12 ◽  
Author(s):  
José Hélio Costa ◽  
Gunasekaran Mohanapriya ◽  
Revuru Bharadwaj ◽  
Carlos Noceda ◽  
Karine Leitão Lima Thiers ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
De Novo ◽  
Cell Cycle Control ◽  
Redox Homeostasis ◽  
Transcript Level ◽  
Aerobic Fermentation ◽  
General Observation ◽  
Alpha Tubulin

In a perspective entitled ‘From plant survival under severe stress to anti-viral human defense’ we raised and justified the hypothesis that transcript level profiles of justified target genes established from in vitro somatic embryogenesis (SE) induction in plants as a reference compared to virus-induced profiles can identify differential virus signatures that link to harmful reprogramming. A standard profile of selected genes named ‘ReprogVirus’ was proposed for in vitro-scanning of early virus-induced reprogramming in critical primary infected cells/tissues as target trait. For data collection, the ‘ReprogVirus platform’ was initiated. This initiative aims to identify in a common effort across scientific boundaries critical virus footprints from diverse virus origins and variants as a basis for anti-viral strategy design. This approach is open for validation and extension. In the present study, we initiated validation by experimental transcriptome data available in public domain combined with advancing plant wet lab research. We compared plant-adapted transcriptomes according to ‘RegroVirus’ complemented by alternative oxidase (AOX) genes during de novo programming under SE-inducing conditions with in vitro corona virus-induced transcriptome profiles. This approach enabled identifying a major complex trait for early de novo programming during SARS-CoV-2 infection, called ‘CoV-MAC-TED’. It consists of unbalanced ROS/RNS levels, which are connected to increased aerobic fermentation that links to alpha-tubulin-based cell restructuration and progression of cell cycle. We conclude that anti-viral/anti-SARS-CoV-2 strategies need to rigorously target ‘CoV-MAC-TED’ in primary infected nose and mouth cells through prophylactic and very early therapeutic strategies. We also discuss potential strategies in the view of the beneficial role of AOX for resilient behavior in plants. Furthermore, following the general observation that ROS/RNS equilibration/redox homeostasis is of utmost importance at the very beginning of viral infection, we highlight that ‘de-stressing’ disease and social handling should be seen as essential part of anti-viral/anti-SARS-CoV-2 strategies.

scholarly journals Overexpression of quality control proteins reduces prion conversion in prion-infected cells

2018 ◽  
Vol 293 (41) ◽  
pp. 16069-16082 ◽  
Author(s):  
Simrika Thapa ◽  
Basant Abdulrahman ◽  
Dalia H. Abdelaziz ◽  
Li Lu ◽  
Manel Ben Aissa ◽  
...  
Keyword(s):  
Quality Control ◽  
De Novo ◽  
Prion Diseases ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Control Mechanisms ◽  
Cellular Mechanisms ◽  
Prion Propagation ◽  
Infected Cells

Prion diseases are fatal infectious neurodegenerative disorders in humans and other animals and are caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. These diseases have the potential to transmit within or between species, including zoonotic transmission to humans. Elucidating the molecular and cellular mechanisms underlying prion propagation and transmission is therefore critical for developing molecular strategies for disease intervention. We have shown previously that impaired quality control mechanisms directly influence prion propagation. In this study, we manipulated cellular quality control pathways in vitro by stably and transiently overexpressing selected quality control folding (ERp57) and cargo (VIP36) proteins and investigated the effects of this overexpression on prion propagation. We found that ERp57 or VIP36 overexpression in persistently prion-infected neuroblastoma cells significantly reduces the amount of PrPSc in immunoblots and prion-seeding activity in the real-time quaking-induced conversion (RT-QuIC) assay. Using different cell lines infected with various prion strains confirmed that this effect is not cell type– or prion strain–specific. Moreover, de novo prion infection revealed that the overexpression significantly reduced newly formed PrPSc in acutely infected cells. ERp57-overexpressing cells significantly overcame endoplasmic reticulum stress, as revealed by expression of lower levels of the stress markers BiP and CHOP, accompanied by a decrease in PrP aggregates. Furthermore, application of ERp57-expressing lentiviruses prolonged the survival of prion-infected mice. Taken together, improved cellular quality control via ERp57 or VIP36 overexpression impairs prion propagation and could be utilized as a potential therapeutic strategy.

scholarly journals Fatal Elephant Endotheliotropic Herpesvirus Infection of Two Young Asian Elephants

2019 ◽  
Vol 7 (10) ◽  
pp. 396 ◽  
Author(s):  
Selvaraj Pavulraj ◽  
Kathrin Eschke ◽  
Adriane Prahl ◽  
Michael Flügger ◽  
Jakob Trimpert ◽  
...  
Keyword(s):  
Genome Sequence ◽  
De Novo ◽  
Limited Information ◽  
Asian Elephants ◽  
Dense Bodies ◽  
Viral Particles ◽  
Infected Cells ◽  
Haemorrhagic Disease ◽  
Generation Sequencing

Elephant endotheliotropic herpesvirus (EEHV) can cause a devastating haemorrhagic disease in young Asian elephants worldwide. Here, we report the death of two young Asian elephants after suffering from acute haemorrhagic disease due to EEHV-1A infection. We detected widespread distribution of EEHV-1A in various organs and tissues of the infected elephants. Enveloped viral particles accumulated within and around cytoplasmic electron-dense bodies in hepatic endothelial cells were detected. Attempts to isolate the virus on different cell cultures showed limited virus replication; however, late viral protein expression was detected in infected cells. We further showed that glycoprotein B (gB) of EEHV-1A possesses a conserved cleavage site Arg-X-Lys/Arg-Arg that is targeted by the cellular protease furin, similar to other members of the Herpesviridae. We have determined the complete 180 kb genome sequence of EEHV-1A isolated from the liver by next-generation sequencing and de novo assembly. As virus isolation in vitro has been unsuccessful and limited information is available regarding the function of viral proteins, we have attempted to take the initial steps in the development of suitable cell culture system and virus characterization. In addition, the complete genome sequence of an EEHV-1A in Europe will facilitate future studies on the epidemiology and diagnosis of EEHV infection in elephants.

scholarly journals Specific Ablation of Antiviral Gene Expression in Macrophages by Antibody-Dependent Enhancement of Ross River Virus Infection

2000 ◽  
Vol 74 (18) ◽  
pp. 8376-8381 ◽  
Author(s):  
Brett A. Lidbury ◽  
Surendran Mahalingam
Keyword(s):  
De Novo ◽  
Viral Disease ◽  
Ross River Virus ◽  
Indigenous Australian ◽  
Antibody Dependent Enhancement ◽  
Antiviral Genes ◽  
Epidemic Polyarthritis ◽  
Infected Cells ◽  
Oxide Synthase

ABSTRACT Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-κB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.

scholarly journals Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

2021 ◽  
Author(s):  
Rui Yang ◽  
Wenzhe Wang ◽  
Meichen Dong ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Target Genes ◽  
De Novo ◽  
Inhibitory Effect ◽  
Nucleotide Synthesis ◽  
High Level ◽  
The Impact

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

scholarly journals The retromer is co-opted to deliver lipid enzymes for the biogenesis of lipid-enriched tombusviral replication organelles

2020 ◽  
Vol 118 (1) ◽  
pp. e2016066118
Author(s):  
Zhike Feng ◽  
Jun-ichi Inaba ◽  
Peter D. Nagy
Keyword(s):  
Lipid Membrane ◽  
De Novo ◽  
In Planta ◽  
Retromer Complex ◽  
Infected Cells ◽  
Surrogate Host ◽  
Positive Strand Rna ◽  
Phosphatidylinositol 4 ◽  
Phosphatidylinositol 3

Biogenesis of viral replication organelles (VROs) is critical for replication of positive-strand RNA viruses. In this work, we demonstrate that tomato bushy stunt virus (TBSV) and the closely related carnation Italian ringspot virus (CIRV) hijack the retromer to facilitate building VROs in the surrogate host yeast and in plants. Depletion of retromer proteins, which are needed for biogenesis of endosomal tubular transport carriers, strongly inhibits the peroxisome-associated TBSV and the mitochondria-associated CIRV replication in yeast and in planta. In vitro reconstitution revealed the need for the retromer for the full activity of the viral replicase. The viral p33 replication protein interacts with the retromer complex, including Vps26, Vps29, and Vps35. We demonstrate that TBSV p33-driven retargeting of the retromer into VROs results in delivery of critical retromer cargoes, such as 1) Psd2 phosphatidylserine decarboxylase, 2) Vps34 phosphatidylinositol 3-kinase (PI3K), and 3) phosphatidylinositol 4-kinase (PI4Kα-like). The recruitment of these cellular enzymes by the co-opted retromer is critical for de novo production and enrichment of phosphatidylethanolamine phospholipid, phosphatidylinositol-3-phosphate [PI(3)P], and phosphatidylinositol-4-phosphate [PI(4)P] phosphoinositides within the VROs. Co-opting cellular enzymes required for lipid biosynthesis and lipid modifications suggest that tombusviruses could create an optimized lipid/membrane microenvironment for efficient VRO assembly and protection of the viral RNAs during virus replication. We propose that compartmentalization of these lipid enzymes within VROs helps tombusviruses replicate in an efficient milieu. In summary, tombusviruses target a major crossroad in the secretory and recycling pathways via coopting the retromer complex and the tubular endosomal network to build VROs in infected cells.

scholarly journals Revealing the host antiviral protein ZAP-S as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting

2021 ◽  
Author(s):  
Matthias Michael Zimmer ◽  
Anuja Nitin Kibe ◽  
Ulfert Rand ◽  
Lukas Pekarek ◽  
Luca Cicin-Sain ◽  
...  
Keyword(s):  
Single Molecule ◽  
De Novo ◽  
Specific Inhibitor ◽  
Antiviral Protein ◽  
Ribosomal Frameshifting ◽  
Reading Frame ◽  
Rna Molecules ◽  
Cellular Factors ◽  
Infected Cells

Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses including SARS-CoV-2, which allows production of essential structural and replicative enzymes from an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshifting RNA molecules and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the host proteome and the SARS-CoV-2 frameshift element. Here, we reveal that zinc-finger antiviral protein (ZAP-S) is a direct and specific regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and ribosomes and interferes with the folding of the frameshift RNA. Together these data illuminate ZAP-S as de novo host-encoded specific inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.

scholarly journals Integrin α4β7 Is Downregulated on the Surfaces of Simian Immunodeficiency Virus SIVmac239-Infected Cells

2010 ◽  
Vol 84 (13) ◽  
pp. 6344-6351 ◽  
Author(s):  
Melisa L. Budde ◽  
Jennifer J. Lhost ◽  
Dawn M. Dudley ◽  
Eva G. Rakasz ◽  
David H. O'Connor
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Immune Evasion ◽  
Lymphoid Tissue ◽  
De Novo ◽  
Ex Vivo ◽  
Viral Proteins ◽  
Flow Cytometry Assay ◽  
Immunodeficiency Virus ◽  
Infected Cells

ABSTRACT Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infection results in an early and enduring depletion of intestinal CD4+ T cells. SIV and HIV bind integrin α4β7, thereby facilitating infection of lymphocytes that home to the gut-associated lymphoid tissue (GALT). Using an ex vivo flow cytometry assay, we found that SIVmac239-infected cells expressed significantly lower levels of integrin α4β7 than did uninfected cells. This finding suggested a potential viral effect on integrin α4β7 expression. Using an in vitro model, we confirmed that integrin α4β7 was downregulated on the surfaces of SIVmac239-infected cells. Further, modulation of integrin α4β7 was dependent on de novo synthesis of viral proteins, but neither cell death, the release of a soluble factor, nor a change in activation state was involved. Downregulation of integrin α4β7 may have an unappreciated role in the CD4 depletion of the mucosal-associated lymphoid compartments, susceptibility to superinfection, and/or immune evasion.

scholarly journals Effect of Vietnamese Helicobactor pylori strain DN18 on the NF-κB pathway and H2AX activation of the AGS cell line

2020 ◽  
Vol 4 (2) ◽  
pp. First
Author(s):  
Dao Thi Hong Pham ◽  
Trang My Ho Nguyen ◽  
Vy Thuy Nguyen
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Strand Break ◽  
Gastric Carcinogenesis ◽  
Mucosal Cell ◽  
Geographical Regions ◽  
Infected Cells ◽  
H Pylori ◽  
The Impact

Infection with Helicobacter pylori (H. pylori) is the strongest known risk factor for gastric cancer. The molecular mechanisms of H. pylori-associated gastric carcinogenesis remain not elucidated. Recent findings indicate that H. pylori infection may promote gastric carcinogenesis by inducing inflammation and genetic instability in gastric epithelial cells. In addition, it is shown that the impact of H. pylori on infected cells is associated with bacterial virulence that is diverse among geographical regions as well as populations. Therefore, we aimed to investigate the effect of H. pylori strain DN18 from Vietnamese subject on the in vitro activity of NF-κB transcription factor, a key regulator of inflammation, and expression of its target genes in this study. Moreover, host genomic instabilities were studied through examining the formation of DNA double-strand break (DSB) by using phosphorylated histone H2AX (γH2AX) as a DSB marker. Our results showed that H. pylori strain DN18 induced activation of NF-kB pathway and increased transcriptional expression of inflammatory mediators in human gastric mucosal cell AGS. We also provided evidence that the H. pylori infection triggered accumulation of  DSBs marker γH2AX. In summary, our study showed the potential ability to cause inflammation and DNA damage to infected cells of H. pylori strains isolated from Vietnamese patients.

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