The Role of Hox Proteins and Interferon Regulatory Factors in Myeloid Differentiation.

During myelopoiesis, differentiating phagocytes develop functional competence and undergo proliferation arrest and eventual programmed cell death. This process involves transcriptional regulation of genes which mediate the innate immune response, mitotic arrest, and apoptosis. A number of transcription factor families play important roles in regulating such genes, including Hox proteins and interferon regulatory factors (IRFs). Disordered expression of Hox proteins is associated with myeloid leukemogenesis. Hox proteins are homeodomain transcription factors that are organized in four paralog groups (A–D). Expression of HoxA7-11 (the ABD-HOXA genes) is characteristic of myeloid progenitors. ABD-HOXA transcription decreases with CD34+ to CD34− progression, and persistent expression of these genes is found in poor prognosis leukemia. Abd Hox proteins regulate genes that are involved in multiple aspects of myelopoiesis. For example, HoxA10 represses transcription of the genes encoding gp91phox and p67phox in myeloid progenitors (the CYBB and NCF2 genes, respectively). In contrast, HoxA9 activates transcription of these genes as differentiation proceeds. Since these are the rate-limiting NADPH oxidase components, HoxA proteins influence the innate immune response. HoxA10 activates transcription of the gene encoding Beta3 integrin, thereby further facilitating NADPH oxidase activation and influencing adhesion. HoxA10 also activates transcription of DUSP4, the gene encoding MAP kinase phosphatase 2 (Mkp2). Mkp2 antagonizes the activity of c-Jun N-terminal kinases (Jnk). Since HoxA10-activation of DUSP4 decreases during myelopoiesis, decreased Mkp2 expression in mature phagocytes facilitates apoptosis via Jnk. Interferon regulatory factors (IRF) also regulate multiple aspects of myelopoiesis. IRF1 and ICSBP/IRF8 activate transcription of the CYBB and NCF2 genes in cooperation with the ets protein PU.1. ICSBP/IRF8 also contributes to phagocyte function by activating genes encoding TLR4, IL12, and Nramp. Additionally, IRF proteins regulate cell cycle progression and proliferation. IRF2, ICSBP/IRF8, and PU.1 activate transcription of gene encoding Neurofibromin 1, thereby downregulating the proliferative response to cytokines such as GM-CSF, M-CSF, and G-CSF. ICSBP/IRF8 and PU.1 also activate the gene encoding Ink4b, thereby also influencing proliferation. In myeloid progenitors, ICSBP/IRF8 influences cell survival by repressing transcription of PTPN13, the gene encoding Fas-associated phosphatase 1 (Fap1), a Fas-antagonist. Decreased ICSBP/IRF8-induced PTPN13 repression during myelopoiesis increases susceptibility of mature phagocytes to Fas-induced apoptosis. Such studies reveal that multiple aspects of myelopoiesis are regulated by common sets of transcription factors. This may suggest therapeutic targets for myeloid leukemias or other disorders of myeloid development.

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Interferon Regulatory Factors and the Atypical IKK-Related Kinases TBK1 and IKK-ε: Essential Players in the Innate Immune Response to RNA Virus Infection

Cellular Signaling and Innate Immune Responses to RNA Virus Infections ◽

10.1128/9781555815561.ch5 ◽

2014 ◽

pp. 51-74

Author(s):

Meztli Arguello ◽

Suzanne Paz ◽

John Hiscott

Keyword(s):

Immune Response ◽

Virus Infection ◽

Innate Immune Response ◽

Rna Virus ◽

Innate Immune ◽

Regulatory Factors ◽

Interferon Regulatory Factors

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High content screening and computational prediction reveal viral genes that suppress innate immune response

10.1101/2021.12.14.472572 ◽

2021 ◽

Author(s):

Tai L Ng ◽

Erika J Olson ◽

Tae Yeon Yoo ◽

H. Sloane Weiss ◽

Yukiye Koide ◽

...

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Nuclear Transport ◽

Computational Prediction ◽

Viral Proteins ◽

Innate Immune ◽

Type I ◽

Viral Genes ◽

Genes Encoding

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins.

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Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Journal of General Virology ◽

10.1099/vir.0.055921-0 ◽

2013 ◽

Vol 94 (11) ◽

pp. 2367-2392 ◽

Cited By ~ 185

Author(s):

Geoffrey L. Smith ◽

Camilla T. O. Benfield ◽

Carlos Maluquer de Motes ◽

Michela Mazzon ◽

Stuart W. J. Ember ◽

...

Keyword(s):

Immune Response ◽

Vaccinia Virus ◽

Innate Immune Response ◽

Immune Evasion ◽

Mammalian Cells ◽

Innate Immune ◽

Gene Encoding ◽

Cytokines And Chemokines ◽

Host Innate Immune Response ◽

New Hosts

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed.

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Bromodomain Containing Protein 4 (BRD4) Regulates Expression of its Interacting Coactivators in the Innate Response to Respiratory Syncytial Virus

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.728661 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xiaofang Xu ◽

Morgan Mann ◽

Dianhua Qiao ◽

Yi Li ◽

Jia Zhou ◽

...

Keyword(s):

Immune Response ◽

Extracellular Matrix ◽

Transcription Factors ◽

Respiratory Syncytial Virus ◽

Innate Immune Response ◽

Airway Epithelial Cells ◽

Innate Immune ◽

Airway Epithelial ◽

Gene Regulatory ◽

Syncytial Virus

Bromodomain-containing protein 4 plays a central role in coordinating the complex epigenetic component of the innate immune response. Previous studies implicated BRD4 as a component of a chromatin-modifying complex that is dynamically recruited to a network of protective cytokines by binding activated transcription factors, polymerases, and histones to trigger their rapid expression via transcriptional elongation. Our previous study extended our understanding of the airway epithelial BRD4 interactome by identifying over 100 functionally important coactivators and transcription factors, whose association is induced by respiratory syncytial virus (RSV) infection. RSV is an etiological agent of recurrent respiratory tract infections associated with exacerbations of chronic obstructive pulmonary disease. Using a highly selective small-molecule BRD4 inhibitor (ZL0454) developed by us, we extend these findings to identify the gene regulatory network dependent on BRD4 bromodomain (BD) interactions. Human small airway epithelial cells were infected in the absence or presence of ZL0454, and gene expression profiling was performed. A highly reproducible dataset was obtained which indicated that BRD4 mediates both activation and repression of RSV-inducible gene regulatory networks controlling cytokine expression, interferon (IFN) production, and extracellular matrix remodeling. Index genes of functionally significant clusters were validated independently. We discover that BRD4 regulates the expression of its own gene during the innate immune response. Interestingly, BRD4 activates the expression of NFκB/RelA, a coactivator that binds to BRD4 in a BD-dependent manner. We extend this finding to show that BRD4 also regulates other components of its functional interactome, including the Mediator (Med) coactivator complex and the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) subunits. To provide further insight into mechanisms for BRD4 in RSV expression, we mapped 7,845 RSV-inducible Tn5 transposase peaks onto the BRD4-dependent gene bodies. These were located in promoters and introns of cytostructural and extracellular matrix (ECM) formation genes. These data indicate that BRD4 mediates the dynamic response of airway epithelial cells to RNA infection by modulating the expression of its coactivators, controlling the expression of host defense mechanisms and remodeling genes through changes in promoter accessibility.

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Identification of PGN_1123 as the Gene Encoding Lipid A Deacylase, an Enzyme Required for Toll-Like Receptor 4 Evasion, inPorphyromonas gingivalis

Journal of Bacteriology ◽

10.1128/jb.00683-18 ◽

2019 ◽

Vol 201 (11) ◽

Cited By ~ 3

Author(s):

Sumita Jain ◽

Ana M. Chang ◽

Manjot Singh ◽

Jeffrey S. McLean ◽

Stephen R. Coats ◽

...

Keyword(s):

Immune Response ◽

Porphyromonas Gingivalis ◽

Innate Immune Response ◽

Lipid A ◽

Innate Immune ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Gene Encoding ◽

Content Type ◽

Chronic Inflammatory Condition

ABSTRACTRemoval of one acyl chain from bacterial lipid A by deacylase activity is a mechanism used by many pathogenic bacteria to evade the host's Toll-like receptor 4 (TLR4)-mediated innate immune response. InPorphyromonas gingivalis, a periodontal pathogen, lipid A deacylase activity converts a majority of the initially synthesized penta-acylated lipid A, a TLR4 agonist, to tetra-acylated structures, which effectively evade TLR4 sensing by being either inert or antagonistic at TLR4. In this paper, we report successful identification of the gene that encodes theP. gingivalislipid A deacylase enzyme. This gene, PGN_1123 inP. gingivalis33277, is highly conserved withinP. gingivalis, and putative orthologs are phylogenetically restricted to theBacteroidetesphylum. Lipid A of ΔPGN_1123 mutants is penta-acylated and devoid of tetra-acylated structures, and the mutant strain provokes a strong TLR4-mediated proinflammatory response, in contrast to the negligible response elicited by wild-typeP. gingivalis. Heterologous expression of PGN_1123 inBacteroides thetaiotaomicronpromoted lipid A deacylation, confirming that PGN_1123 encodes the lipid A deacylase enzyme.IMPORTANCEPeriodontitis, commonly referred to as gum disease, is a chronic inflammatory condition that affects a large proportion of the population.Porphyromonas gingivalisis a bacterium closely associated with periodontitis, although how and if it is a cause for the disease are not known. It has a formidable capacity to dampen the host's innate immune response, enabling its persistence in diseased sites and triggering microbial dysbiosis in animal models of infection.P. gingivalisis particularly adept at evading the host's TLR4-mediated innate immune response by modifying the structure of lipid A, the TLR4 ligand. In this paper, we report identification of the gene encoding lipid A deacylase, a key enzyme that modifies lipid A to TLR4-evasive structures.

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Analysis of the basal colonic innate immune response of pigs divergent in feed efficiency and following an ex vivo lipopolysaccharide challenge

Physiological Genomics ◽

10.1152/physiolgenomics.00013.2019 ◽

2019 ◽

Vol 51 (9) ◽

pp. 443-448 ◽

Cited By ~ 4

Author(s):

Stafford Vigors ◽

John V. O’ Doherty ◽

Marion Ryan ◽

Torres Sweeney

Keyword(s):

Immune Response ◽

Innate Immune Response ◽

Feed Efficiency ◽

Ex Vivo ◽

Innate Immune ◽

Colonic Tissue ◽

Experimental Conditions ◽

Defense Proteins ◽

Lps Challenge ◽

Genes Encoding

While feed efficiency is influenced by multiple physiological processes, it is not known how efficient and inefficient pigs differ in relation to their basal immune response, and particularly their innate immune response to a microbial challenge. Hence, the objective was to examine the expression of genes encoding innate immune response markers in basal colonic tissue and colonic tissue following an ex vivo lipopolysaccharide (LPS) challenge from pigs divergent in residual feed intake (RFI). Pigs that differed in RFI were selected from two different farms of origin. Colonic tissue was harvested from high RFI (HRFI) and low (LRFI) pigs, and two experimental conditions were explored: the first was basal unchallenged tissue and the second was colonic tissue following an ex vivo LPS challenge. RNA was extracted and tested on a Nanostring panel of 72 genes coding for barrier defense proteins, transmembrane receptors, kinases, transcription regulators, cytokines, and cytokine regulators. In the basal unchallenged tissue, the LRFI pigs had increased expression of AOAH, AP1, and TRAM and the cytokines TNF, IL10, and CXCL8, compared with the HRFI pigs ( P < 0.05), with a significant effect of farm of origin on 31 genes ( P < 0.05). In the LPS-challenged tissues, the LRFI group had higher expression of TLR1, TLR7, TLR8, GPR43/FFAR2, JAK2, and NFAM1 compared with the HRFI group ( P < 0.05). In conclusion, these data suggest that LRFI pigs have an upregulated basal colonic inflammatory state and a heightened response to an LPS challenge compared with the inefficient HRFI pigs. This immune profile potentially enhances their capacity to respond to an infectious challenge.

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MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract

Cytokine ◽

10.1016/j.cyto.2019.154895 ◽

2020 ◽

Vol 126 ◽

pp. 154895 ◽

Cited By ~ 27

Author(s):

Bandar Alosaimi ◽

Maaweya E. Hamed ◽

Asif Naeem ◽

Ali A. Alsharef ◽

Saeed Y. AlQahtani ◽

...

Keyword(s):

Immune Response ◽

Respiratory Tract ◽

Innate Immune Response ◽

Lower Respiratory Tract ◽

Innate Immune ◽

Th2 Cytokines ◽

Genes Encoding ◽

Th1 And Th2 Cytokines ◽

Th1 And Th2

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Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system

The Journal of Cell Biology ◽

10.1083/jcb.200301097 ◽

2003 ◽

Vol 162 (2) ◽

pp. 257-268 ◽

Cited By ~ 56

Author(s):

Denis Soulet ◽

Serge Rivest

Keyword(s):

Central Nervous System ◽

Immune Response ◽

Nervous System ◽

Innate Immune Response ◽

Transcriptional Activation ◽

Critical Role ◽

Innate Immune ◽

Genes Encoding ◽

Factor Α ◽

Mouse Central Nervous System

The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor α and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

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