Innate immune gene expression in Acropora palmata is consistent despite variance in yearly disease events

AbstractCoral disease outbreaks are expected to increase in prevalence, frequency and severity due to climate change and other anthropogenic stressors. This is especially worrying for the Caribbean branching Acropora palmata which has already seen an 80% decrease in its coral cover, with this primarily due to disease. Despite the importance of this species, there has yet to be a characterization of its transcriptomic response to disease exposure. In this study we provide the first transcriptomic analysis of 12 A. palmata genotypes, and their symbiont Symbiodiniaceae, exposed to disease in 2016 and 2017. Year was the primary driver of sample variance for A. palmata and the Symbiodiniaceae. Lower expression of ribosomal genes in the coral, and higher expression of transmembrane ion transport genes in the Symbiodiniaceae indicate that the increased virulence in 2017 may have been due to a dysbiosis between the coral and Symbiodiniaceae. We also identified a conserved suite of innate immune genes responding to the disease challenge that was activated in both years. This included genes from the Toll-like receptor and lectin pathways, and antimicrobial peptides. Co-expression analysis identified a module positively correlated to disease exposure rich in innate immune genes, with D-amino acid oxidase, a gene implicated in phagocytosis and microbiome homeostasis, as the hub gene. The role of D-amino acid oxidase in coral immunity has not been characterized but holds potential as an important enzyme for responding to disease. Our results indicate that A. palmata mounts a similar immune response to disease exposure as other coral species previously studied, but with unique features that may be critical to the survival of this keystone Caribbean species.

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Human Papillomavirus 16 E6 and E7 Synergistically Repress Innate Immune Gene Transcription

mSphere ◽

10.1128/msphere.00828-19 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 10

Author(s):

Claire D. James ◽

Christian T. Fontan ◽

Raymonde Otoa ◽

Dipon Das ◽

Apurva T. Prabhakar ◽

...

Keyword(s):

Viral Proteins ◽

Innate Immune ◽

Cellular Growth ◽

Immune Gene ◽

Human Papillomavirus 16 ◽

Immune Genes ◽

Hpv16 Genome ◽

E6 And E7 ◽

Innate Immune Genes

ABSTRACT Human papillomaviruses (HPV) are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently, we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells overexpressing the viral proteins, and to further investigate the role of individual viral proteins in this repression, we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually is not sufficient to repress IIG expression in the context of the entire HPV16 genome; both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in HPV16-positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies led us to the following model. Viral replication per se can activate the DDR following infection, and this activation is a known inducer of IIG expression, which may induce cellular senescence. To combat this, E6 and E7 synergistically combine to manipulate the DDR and actively repress innate immune gene expression promoting cellular growth; neither protein by itself is able to do this. IMPORTANCE The role of human papillomavirus 16 (HPV16) in human cancers is well established; however, to date there are no antiviral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance the understanding of the viral life cycle. Innate immune genes (IIGs) are repressed by HPV16, and we have reported that this repression persists through to cancer. Reversal of this repression would boost the immune response to HPV16-positive tumors, an area that is becoming more important given the advances in immunotherapy. This report demonstrates that E6 and E7 synergistically repress IIG expression in the context of the entire HPV16 genome. Removal of either protein activates the expression of IIGs by HPV16. Therefore, gaining a precise understanding of how the viral oncogenes repress IIG expression represents an opportunity to reverse this repression and boost the immune response to HPV16 infections for therapeutic gain.

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Global transcriptomics analyses reveal specialized roles for splicing regulatory proteins in the macrophage innate immune response

10.1101/2020.12.06.413690 ◽

2020 ◽

Author(s):

KO West ◽

AR Wagner ◽

HM Scott ◽

KJ Vail ◽

K Carter ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Regulatory Proteins ◽

Raw 264.7 ◽

Immune Gene ◽

Post Translational Modification ◽

Immune Genes ◽

Innate Immune Genes

ABSTRACTWhile the signaling cascades and transcription factors that activate gene expression in macrophages following pattern recognition receptor engagement are well known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins undergo dynamic post-translational modification in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We observed that thousands of genes were up or downregulated in SR/hnRNP knockdown cells and differentially expressed genes (DEGs) varied significantly depending on the SR/hnRNP examined. We discovered that a subset of critical innate immune genes (Nos2, Mx1, Il1a) rely heavily on SR/hnRNPs for proper induction and/or repression, while others (Tnf, Il1b) are generally unaffected by splicing factor knockdown. We also discovered that many key immune sensors and signaling molecules are subject to regulation by alternative splicing. While our data does not provide evidence for positive correlation between a transcripts’ reliance of SR/hnRNPs for proper expression and the gene’s induction level, length, or intron/exon architecture, we found that many rapidly induced primary response genes are repressed by SR/hnRNPs. Consistent with SR/hnRNP proteins contributing to innate immune outcomes, knockdown of hnRNP K and U significantly enhanced the ability of RAW 264.7 macrophages to control viral replication. Based on these collective findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, supporting a model wherein pre-splicing is a critical regulatory node in the innate immune response.

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Human papillomavirus 16 E6 and E7 synergistically repress innate immune gene transcription

10.1101/841007 ◽

2019 ◽

Author(s):

Claire D. James ◽

Christian T. Fontan ◽

Raymonde Otoa ◽

Dipon Das ◽

Apurva T. Prabhakar ◽

...

Keyword(s):

Viral Proteins ◽

Innate Immune ◽

Cellular Growth ◽

Immune Gene ◽

Immune Genes ◽

Hpv16 Genome ◽

E6 And E7 ◽

Innate Immune Genes ◽

Innate Immune Gene

AbstractHuman papillomaviruses are causative agents in 5% of all cancers, including the majority of anogenital and oropharyngeal cancers. Downregulation of innate immune genes (IIGs) by HPV to promote the viral life cycle is well documented; E6 and E7 are known repressors of these genes. More recently we demonstrated that E2 could also repress IIGs. These studies have been carried out in cells over-expressing the viral proteins and to further investigate the role of individual viral proteins in this repression we introduced stop codons into E6 and/or E7 in the entire HPV16 genome and generated N/Tert-1 cells stably maintaining the HPV16 genomes. We demonstrate that E6 or E7 individually are not sufficient to repress IIG expression in the context of the entire HPV16 genome, both are required for a synergistic repression. The DNA damage response (DDR) is activated by HPV16 irrespective of E6 and E7 expression, presumably due to viral replication; E1 is a known activator of the DDR. In addition, replication stress was apparent in the HPV16 positive cells lacking E6 and E7, manifested by attenuated cellular growth and activation of replication stress genes. These studies lead us to the following model. Viral replication per se can activate the DDR following infection, and this activation is a known inducer of IIG expression which could induce cellular senescence. To combat this, E6 and E7 synergistically combine to manipulate the DDR and actively repress innate immune gene expression promoting cellular growth; neither protein by itself is able to do this.ImportanceThe role of HPV16 in human cancers is well established; however, to date there are no anti-viral therapeutics that are available for combatting these cancers. To identify such targets, we must enhance understanding of the viral life cycle. Innate immune genes (IIGs) are repressed by HPV16, and we have reported that this repression persists through to cancer. Reversal of this repression would boost the immune response to HPV16 positive tumors, an area that is becoming more important given the advances in immunotherapy. This report demonstrates that E6 and E7 synergistically repress IIG expression in the context of the entire HPV16 genome. Removal of either protein activates the expression of IIGs by HPV16. Therefore, gaining a precise understanding of how the viral oncogenes repress IIG expression represents an opportunity to reverse this repression and boost the immune response to HPV16 infections for therapeutic gain.

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Purification and Characterization of Lupus Anticoagulant Like Protein from Agkistrodon Halys Brevicaudus Venom

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650698 ◽

1996 ◽

Vol 76 (06) ◽

pp. 0993-0997

Author(s):

Zhao-Yan Li ◽

Xiao-Wei Wu ◽

Tie-Fu Yu ◽

Eric C-Y Lian

Keyword(s):

Amino Acid ◽

Lupus Anticoagulant ◽

Inhibitory Effect ◽

Clotting Factor ◽

Acid Oxidase ◽

Crude Venom ◽

Amino Acid Oxidase ◽

Sds Page ◽

The Individual ◽

Reducing Condition

SummaryBy means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)Q(Q/K). It was devoid of phospho-lipaseA, fibrino(geno)lytic, 5′-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell’s viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.

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Impairment of Platelet Aggregation by Echis colorata Venom Mediated by L-Amino Acid Oxidase or H2O2

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657280 ◽

1982 ◽

Vol 48 (03) ◽

pp. 277-282 ◽

Cited By ~ 22

Author(s):

I Nathan ◽

A Dvilansky ◽

T Yirmiyahu ◽

M Aharon ◽

A Livne

Keyword(s):

Hydrogen Peroxide ◽

Amino Acid ◽

Platelet Aggregation ◽

Snake Venom ◽

Oxidase Activity ◽

Enzyme Preparation ◽

Acid Oxidase ◽

Crude Venom ◽

Amino Acid Oxidase ◽

Hemostatic Disorders

SummaryEchis colorata bites cause impairment of platelet aggregation and hemostatic disorders. The mechanism by which the snake venom inhibits platelet aggregation was studied. Upon fractionation, aggregation impairment activity and L-amino acid oxidase activity were similarly separated from the crude venom, unlike other venom enzymes. Preparations of L-amino acid oxidase from E.colorata and from Crotalus adamanteus replaced effectively the crude E.colorata venom in impairment of platelet aggregation. Furthermore, different treatments known to inhibit L-amino acid oxidase reduced in parallel the oxidase activity and the impairment potency of both the venom and the enzyme preparation. H2O2 mimicked characteristically the impairment effects of L-amino acid oxidase and the venom. Catalase completely abolished the impairment effects of the enzyme and the venom. It is concluded that hydrogen peroxide formed by the venom L-amino acid oxidase plays a role in affecting platelet aggregation and thus could contribute to the extended bleeding typical to persons bitten by E.colorata.

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1080 Milk yield genotype impacts expression of hepatic innate immune genes during the transition period in Holsteins

Journal of Animal Science ◽

10.2527/jam2016-1080 ◽

2016 ◽

Vol 94 (suppl_5) ◽

pp. 518-518

Author(s):

G. T. Cousillas ◽

W. J. Weber ◽

B. Walcheck ◽

D. E. Kerr ◽

T. H. Elsasser ◽

...

Keyword(s):

Milk Yield ◽

Transition Period ◽

Innate Immune ◽

Immune Genes ◽

Innate Immune Genes

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Faculty Opinions recommendation of Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1010617.193306 ◽

2003 ◽

Author(s):

Michael O'Donovan

Keyword(s):

Amino Acid ◽

Human Gene ◽

Physiological Data ◽

Acid Oxidase ◽

Amino Acid Oxidase

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Spinal mechanisms contributing to the development of pain hypersensitivity induced by sphingolipids in the rat

Pharmacological Reports ◽

10.1007/s43440-020-00207-x ◽

2021 ◽

Author(s):

Hong Wei ◽

Zuyue Chen ◽

Ari Koivisto ◽

Antti Pertovaara

Keyword(s):

Amino Acid ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Gap Junction ◽

Male Rats ◽

Acid Oxidase ◽

Amino Acid Oxidase ◽

Mk 801 ◽

Mechanical Hypersensitivity ◽

Pain Hypersensitivity

Abstract Background Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ1 and NMDA receptors, gap junctions and D-amino acid oxidase. Methods Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (σ1 receptor antagonist), carbenoxolone (a gap junction decoupler), MK-801 (NMDA receptor antagonist) and AS-057278 (inhibitor of D-amino acid oxidase, DAAO) were used to prevent the DMS-induced hypersensitivity, and pregnenolone sulphate (TRPM3 agonist) to recapitulate hypersensitivity. Results DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin. Conclusions Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the σ1 and NMDA receptors, and DAAO.

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