scholarly journals Comparative Analyses of Transcriptional Profiles in Mouse Organs Using a Pneumonic Plague Model after Infection with Wild-TypeYersinia pestisCO92 and Its Braun Lipoprotein Mutant

2009 ◽  
Vol 2009 ◽  
pp. 1-16 ◽  
Author(s):  
Cristi L. Galindo ◽  
Scott T. Moen ◽  
Elena V. Kozlova ◽  
Jian Sha ◽  
Harold R. Garner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Host Cell ◽  
Apoptotic Cell ◽  
Cytokine Signaling ◽  
Infection Model ◽  
Transcriptional Responses ◽  
Pneumonic Plague ◽  
Transcriptional Profiles ◽  
Host Cell Apoptosis ◽  
Mechanistic Basis

We employed Murine GeneChips to delineate the global transcriptional profiles of the livers, lungs, and spleens in a mouse pneumonic plague infection model with wild-type (WT)Y. pestisCO92 and its Braun lipoprotein (Δlpp) mutant with reduced virulence. These organs showed differential transcriptional responses to infection with WTY. pestis, but the overall host functional processes affected were similar across all three tissues. Gene expression alterations were found in inflammation, cytokine signaling, and apoptotic cell death-associated genes. Comparison of WT andΔlppmutant-infected mice indicated significant overlap in lipopolysaccharide- (LPS-) associated gene expression, but the absence of Lpp perturbed host cell signaling at critical regulatory junctions resulting in altered immune response and possibly host cell apoptosis. We generated a putative signaling pathway including major inflammatory components that could account for the synergistic action of LPS and Lpp and provided the mechanistic basis of attenuation caused by deletion of thelppgene fromY. pestisin a mouse model of pneumonic plague.

scholarly journals IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes

2018 ◽  
Vol 115 (40) ◽  
pp. 10088-10093 ◽  
Author(s):  
Anne Müller ◽  
André Hennig ◽  
Sebastian Lorscheid ◽  
Paula Grondona ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Proinflammatory Cytokine ◽  
Target Genes ◽  
Immune Cell ◽  
Transcriptional Regulator ◽  
Inflammatory Cells ◽  
Cytokine Signaling ◽  
Transcriptional Responses ◽  
Psoriasis Therapy ◽  
Proinflammatory Gene

Proinflammatory cytokine signaling in keratinocytes plays a crucial role in the pathogenesis of psoriasis, a skin disease characterized by hyperproliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells. Although IL-17A and TNFα are effective therapeutic targets in psoriasis, IL-36 has recently emerged as a proinflammatory cytokine. However, little is known about IL-36 signaling and its downstream transcriptional responses. Here, we found that exposure of keratinocytes to IL-36 induced the expression of IκBζ, an atypical IκB member and a specific transcriptional regulator of selective NF-κB target genes. Induction of IκBζ by IL-36 was mediated by NF-κB and STAT3. In agreement, IL-36–mediated induction of IκBζ was found to be required for the expression of various psoriasis-related genes involved in inflammatory signaling, neutrophil chemotaxis, and leukocyte activation. Importantly, IκBζ-knockout mice were protected against IL-36–mediated dermatitis, accompanied by reduced proinflammatory gene expression, decreased immune cell infiltration, and a lack of keratinocyte hyperproliferation. Moreover, expression of IκBζ mRNA was highly up-regulated in biopsies of psoriasis patients where it coincided withIL36Glevels. Thus our results uncover an important role for IκBζ in IL-36 signaling and validate IκBζ as an attractive target for psoriasis therapy.

scholarly journals Structural insight into tanapoxvirus mediated inhibition of apoptosis

2020 ◽  
Author(s):  
Chathura D. Suraweera ◽  
Mohd Ishtiaq Anasir ◽  
Srishti Chugh ◽  
Airah Javorsky ◽  
Rachael E. Impey ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Host Cell ◽  
Inhibitory Protein ◽  
Double Stranded Dna ◽  
Host Cell Apoptosis ◽  
Mechanistic Basis ◽  
Binding Groove ◽  
Multicellular Organisms ◽  
Oligomeric Forms ◽  
Insight Into

AbstractPremature programmed cell death or apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Tanapoxvirus (TANV) is a large double-stranded DNA virus belonging to the poxviridae that causes mild Monkeypox-like infections in humans and primates. TANV encodes for a putative apoptosis inhibitory protein 16L. We show that TANV16L is able to bind to a range of peptides spanning the BH3 motif of human pro-apoptotic Bcl-2 proteins, and is able to counter growth arrest of yeast induced by human Bak and Bax. We then determined the crystal structures of TANV16L bound to three identified interactors, Bax, Bim and Puma BH3. TANV16L adopts a globular Bcl-2 fold comprising 7 α-helices, and utilizes the canonical Bcl-2 binding groove to engage pro-apoptotic host cell Bcl-2 proteins. Unexpectedly, TANV16L is able to adopt both a monomeric as well as a domain-swapped dimeric topology where the α1 helix from one protomer is swapped into a neighbouring unit. Despite adopting two different oligomeric forms, the canonical ligand binding groove in TANV16L remains unchanged from monomer to domain-swapped dimer. Our results provide a structural and mechanistic basis for tanapoxvirus mediated inhibition of host cell apoptosis, and reveal the capacity of Bcl-2 proteins to adopt differential oligomeric states whilst maintaining the canonical ligand binding groove in an unchanged state.

scholarly journals The anti-apoptotic Coxiella burnetii effector protein AnkG is a strain specific virulence factor

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Walter Schäfer ◽  
Teresa Schmidt ◽  
Arne Cordsmeier ◽  
Vítor Borges ◽  
Paul A. Beare ◽  
...  
Keyword(s):  
Host Cell ◽  
Coxiella Burnetii ◽  
Cell Apoptosis ◽  
Effector Proteins ◽  
Host Cells ◽  
Infection Model ◽  
Effector Protein ◽  
Host Cell Apoptosis ◽  
Bacterial Replication ◽  
Apoptotic Activity

Abstract The ability to inhibit host cell apoptosis is important for the intracellular replication of the obligate intracellular pathogen Coxiella burnetii, as it allows the completion of the lengthy bacterial replication cycle. Effector proteins injected into the host cell by the C. burnetii type IVB secretion system (T4BSS) are required for the inhibition of host cell apoptosis. AnkG is one of these anti-apoptotic effector proteins. The inhibitory effect of AnkG requires its nuclear localization, which depends on p32-dependent intracellular trafficking and importin-α1-mediated nuclear entry of AnkG. Here, we compared the sequences of ankG from 37 C. burnetii isolates and classified them in three groups based on the predicted protein size. The comparison of the three different groups allowed us to identify the first 28 amino acids as essential and sufficient for the anti-apoptotic activity of AnkG. Importantly, only the full-length protein from the first group is a bona fide effector protein injected into host cells during infection and has anti-apoptotic activity. Finally, using the Galleria mellonella infection model, we observed that AnkG from the first group has the ability to attenuate pathology during in vivo infection, as it allows survival of the larvae despite bacterial replication.

scholarly journals Global Impact of Influenza Virus on Cellular Pathways Is Mediated by both Replication-Dependent and -Independent Events

2001 ◽  
Vol 75 (9) ◽  
pp. 4321-4331 ◽  
Author(s):  
Gary K. Geiss ◽  
Mahru C. An ◽  
Roger E. Bumgarner ◽  
Erick Hammersmark ◽  
Dawn Cunningham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Influenza Virus ◽  
Viral Replication ◽  
Host Cell ◽  
Cellular Response ◽  
Gene Expression Pattern ◽  
Influenza Viruses ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Independent Events

ABSTRACT Influenza virus, the causative agent of the common flu, is a worldwide health problem with significant economic consequences. Studies of influenza virus biology have revealed elaborate mechanisms by which the virus interacts with its host cell as it inhibits the synthesis of cellular proteins, evades the innate antiviral response, and facilitates production of viral RNAs and proteins. With the advent of DNA array technology it is now possible to obtain a large-scale view of how viruses alter the environment within the host cell. In this study, the cellular response to influenza virus infection was examined by monitoring the steady-state mRNA levels for over 4,600 cellular genes. Infections with active and inactivated influenza viruses identified changes in cellular gene expression that were dependent on or independent of viral replication, respectively. Viral replication resulted in the downregulation of many cellular mRNAs, and the effect was enhanced with time postinfection. Interestingly, several genes involved in protein synthesis, transcriptional regulation, and cytokine signaling were induced by influenza virus replication, suggesting that some may play essential or accessory roles in the viral life cycle or the host cell's stress response. The gene expression pattern induced by inactivated viruses revealed induction of the cellular metallothionein genes that may represent a protective response to virus-induced oxidative stress. Genome-scale analyses of virus infections will help us to understand the complexities of virus-host interactions and may lead to the discovery of novel drug targets or antiviral therapies.

scholarly journals Crystal structures of ORFV125 provide insight into orf virus-mediated inhibition of apoptosis

2020 ◽  
Vol 477 (23) ◽  
pp. 4527-4541 ◽  
Author(s):  
Chathura D. Suraweera ◽  
Mark G. Hinds ◽  
Marc Kvansakul
Keyword(s):  
Host Cell ◽  
Crystal Structures ◽  
B Cell Lymphoma ◽  
Orf Virus ◽  
Structural Basis ◽  
Inhibitory Protein ◽  
Affinity Ligand ◽  
Host Cell Apoptosis ◽  
Mechanistic Basis ◽  
Binding Groove

Premature apoptosis of cells is a strategy utilized by multicellular organisms to counter microbial threats. Orf virus (ORFV) is a large double-stranded DNA virus belonging to the poxviridae. ORFV encodes for an apoptosis inhibitory protein ORFV125 homologous to B-cell lymphoma 2 or Bcl-2 family proteins, which has been shown to inhibit host cell encoded pro-apoptotic Bcl-2 proteins. However, the structural basis of apoptosis inhibition by ORFV125 remains to be clarified. We show that ORFV125 is able to bind to a range of peptides spanning the BH3 motif of human pro-apoptotic Bcl-2 proteins including Bax, Bak, Puma and Hrk with modest to weak affinity. We then determined the crystal structures of ORFV125 alone as well as bound to the highest affinity ligand Bax BH3 motif. ORFV125 adopts a globular Bcl-2 fold comprising 7 α-helices, and utilizes the canonical Bcl-2 binding groove to engage pro-apoptotic host cell Bcl-2 proteins. In contrast with a previously predicted structure, ORFV125 adopts a domain-swapped dimeric topology, where the α1 helix from one protomer is swapped into a neighbouring unit. Furthermore, ORFV125 differs from the conserved architecture of the Bcl-2 binding groove and instead of α3 helix forming one of the binding groove walls, ORFV125 utilizes an extended α2 helix that comprises the equivalent region of helix α3. This results in a subtle variation of previously observed dimeric Bcl-2 architectures in other poxvirus and human encoded Bcl-2 proteins. Overall, our results provide a structural and mechanistic basis for orf virus-mediated inhibition of host cell apoptosis.

scholarly journals Transcriptome Analysis of Hypertrophic Heart Tissues from Murine Transverse Aortic Constriction and Human Aortic Stenosis Reveals Key Genes and Transcription Factors Involved in Cardiac Remodeling Induced by Mechanical Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Peng Yu ◽  
Baoli Zhang ◽  
Ming Liu ◽  
Ying Yu ◽  
Ji Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Aortic Stenosis ◽  
Mechanical Stress ◽  
Cardiac Remodeling ◽  
Interaction Network ◽  
Cytokine Signaling ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Genomic Changes

Background. Mechanical stress-induced cardiac remodeling that results in heart failure is characterized by transcriptional reprogramming of gene expression. However, a systematic study of genomic changes involved in this process has not been performed to date. To investigate the genomic changes and underlying mechanism of cardiac remodeling, we collected and analyzed DNA microarray data for murine transverse aortic constriction (TAC) and human aortic stenosis (AS) from the Gene Expression Omnibus database and the European Bioinformatics Institute. Methods and Results. The differential expression genes (DEGs) across the datasets were merged. The Venn diagrams showed that the number of intersections for early and late cardiac remodeling was 74 and 16, respectively. Gene ontology and protein–protein interaction network analysis showed that metabolic changes, cell differentiation and growth, cell cycling, and collagen fibril organization accounted for a great portion of the DEGs in the TAC model, while in AS patients’ immune system signaling and cytokine signaling displayed the most significant changes. The intersections between the TAC model and AS patients were few. Nevertheless, the DEGs of the two species shared some common regulatory transcription factors (TFs), including SP1, CEBPB, PPARG, and NFKB1, when the heart was challenged by applied mechanical stress. Conclusions. This study unravels the complex transcriptome profiles of the heart tissues and highlighting the candidate genes involved in cardiac remodeling induced by mechanical stress may usher in a new era of precision diagnostics and treatment in patients with cardiac remodeling.

scholarly journals Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose

2017 ◽  
Vol 16 ◽  
pp. 117693511774013 ◽  
Author(s):  
Hien H Nguyen ◽  
Susan C Tilton ◽  
Christopher J Kemp ◽  
Mingzhou Song
Keyword(s):  
Gene Expression ◽  
Pathway Analysis ◽  
Dose Response ◽  
Response Analysis ◽  
Response Curves ◽  
Cancer Pathways ◽  
Pathway Gene ◽  
Mechanistic Basis ◽  
Functional Pathway ◽  
Squamous Cell Papilloma

The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis—strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems.

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