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1. The scavenger receptor repertoire in six cnidarian species and its putative role in cnidarian-dinoflagellate symbiosis

   https://doi.org/10.7717/peerj.2692  

   Neubauer, Emilie F. ; Poole, Angela Z. ; Weis, Virginia M. ; Davy, Simon K. ( November 2016 , PeerJ)

   Many cnidarians engage in a mutualism with endosymbiotic photosynthetic dinoflagellates that forms the basis of the coral reef ecosystem. Interpartner interaction and regulation includes involvement of the host innate immune system. Basal metazoans, including cnidarians have diverse and complex innate immune repertoires that are just beginning to be described. Scavenger receptors (SR) are a diverse superfamily of innate immunity genes that recognize a broad array of microbial ligands and participate in phagocytosis of invading microbes. The superfamily includes subclades named SR-A through SR-I that are categorized based on the arrangement of sequence domains including the scavenger receptor cysteine rich (SRCR), the C-type lectin (CTLD) and the CD36 domains. Previous functional and gene expression studies on cnidarian-dinoflagellate symbiosis have implicated SR-like proteins in interpartner communication and regulation. In this study, we characterized the SR repertoire from a combination of genomic and transcriptomic resources from six cnidarian species in the Class Anthozoa. We combined these bioinformatic analyses with functional experiments using the SR inhibitor fucoidan to explore a role for SRs in cnidarian symbiosis and immunity. Bioinformatic searches revealed a large diversity of SR-like genes that resembled SR-As, SR-Bs, SR-Es and SR-Is. SRCRs, CTLDs and CD36 domains were identified in multiple sequences in combinations that were highly homologous to vertebrate SRs as well as in proteins with novel domain combinations. Phylogenetic analyses of CD36 domains of the SR-B-like sequences from a diversity of metazoans grouped cnidarian with bilaterian sequences separate from other basal metazoans. All cnidarian sequences grouped together with moderate support in a subclade separately from bilaterian sequences. Functional experiments were carried out on the sea anemoneAiptasia pallidathat engages in a symbiosis withSymbiodinium minutum(clade B1). Experimental blocking of the SR ligand binding site with the inhibitor fucoidan reduced the ability ofS. minutumto colonizeA. pallidasuggesting that host SRs play a role in host-symbiont recognition. In addition, incubation of symbiotic anemones with fucoidan elicited an immune response, indicating that host SRs function in immune modulation that results in host tolerance of the symbionts.

    

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2. Differential gene expression analysis of symbiotic and aposymbiotic Exaiptasia anemones under immune challenge with Vibrio coralliilyticus

   https://doi.org/10.1002/ece3.5403  

   Roesel, Charles L. ; Vollmer, Steven V. ( June 2019 , Ecology and Evolution)

   Anthozoans are a class of Cnidarians that includes scleractinian corals, anemones, and their relatives. Despite a global rise in disease epizootics impacting scleractinian corals, little is known about the immune response of this key group of invertebrates. To better characterize the anthozoan immune response, we used the model anemoneExaiptasia pallidato explore the genetic links between the anthozoan–algal symbioses and immunity in a two‐factor RNA‐Seq experiment using both symbiotic and aposymbiotic (menthol‐bleached)Exaiptasia pallidaexposed to the bacterial pathogenVibrio coralliilyticus. Multivariate and univariate analyses ofExaiptasiagene expression demonstrated that exposure to liveVibrio coralliilyticushad strong and significant impacts on transcriptome‐wide gene expression for both symbiotic and aposymbiotic anemones, but we did not observe strong interactions between symbiotic state andVibrioexposure. There were 4,164 significantly differentially expressed (DE) genes forVibrioexposure, 1,114 DE genes for aposymbiosis, and 472 DE genes for the additive combinations ofVibrioand aposymbiosis. KEGG enrichment analyses identified 11 pathways—involved in immunity (5), transport and catabolism (4), and cell growth and death (2)—that were enriched due to bothVibrioand/or aposymbiosis. Immune pathways showing strongest differential expression included complement, coagulation, nucleotide‐binding, and oligomerization domain (NOD), and Toll forVibrioexposure and coagulation and apoptosis for aposymbiosis.

    

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3. Immunogenic Cell Death: A Step Ahead of Autophagy in Cancer Therapy

   Gupta, Gourab ; Borglum, Kristina ; Chen, Hexin ( March 2021 , Journal of cancer immunology)

   null (Ed.)

   Immunogenic cell death (ICD) plays a major role in providing long lasting protective antitumor immunity by the chronic exposure of damage associated molecular patterns (DAMPs) in the tumor microenvironment (TME). DAMPs are essential for attracting immunogenic cells to the TME, maturation of DCs, and proper presentation of tumor antigens to the T cells so they can kill more cancer cells. Thus for the proper release of DAMPs, a controlled mechanism of cell death is necessary. Drug induced tumor cell killing occurs by apoptosis, where in autophagy may act as a shield protecting the tumor cells and sometimes providing multi-drug resistance to chemotherapeutics. However, autophagy is required for the release of ATP as it remains one of the key DAMPs for the induction of ICD. In this review, we discuss the intricate balance between autophagy and apoptosis and the various strategies that we can apply to make these immunologically silent processes immunogenic. There are several steps of autophagy and apoptosis that can be regulated to generate an immune response. The genes involved in the processes can be regulated by drugs or inhibitors to amplify the effects of ICD and therefore serve as potential therapeutic targets. 

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4. Starvation differentially affects gene expression, immunity and pathogen susceptibility across symbiotic states in a model cnidarian

   https://doi.org/10.1098/rspb.2023.1685  

   Valadez-Ingersoll, Maria ; Aguirre Carrión, Pablo J. ; Bodnar, Caoimhe A. ; Desai, Niharika A. ; Gilmore, Thomas D. ; Davies, Sarah W. ( February 2024 , Proceedings of the Royal Society B: Biological Sciences)

   Mutualistic symbioses between cnidarians and photosynthetic algae are modulated by complex interactions between host immunity and environmental conditions. Here, we investigate how symbiosis interacts with food limitation to influence gene expression and stress response programming in the sea anemoneExaiptasia pallida(Aiptasia). Transcriptomic responses to starvation were similar between symbiotic and aposymbiotic Aiptasia; however, aposymbiotic anemone responses were stronger. Starved Aiptasia of both symbiotic states exhibited increased protein levels of immune-related transcription factor NF-κB, its associated gene pathways, and putative target genes. However, this starvation-induced increase in NF-κB correlated with increased immunity only in symbiotic anemones. Furthermore, starvation had opposite effects on Aiptasia susceptibility to pathogen and oxidative stress challenges, suggesting distinct energetic priorities under food scarce conditions. Finally, when we compared starvation responses in Aiptasia to those of a facultative coral and non-symbiotic anemone, ‘defence’ responses were similarly regulated in Aiptasia and the facultative coral, but not in the non-symbiotic anemone. This pattern suggests that capacity for symbiosis influences immune responses in cnidarians. In summary, expression of certain immune pathways—including NF-κB—does not necessarily predict susceptibility to pathogens, highlighting the complexities of cnidarian immunity and the influence of symbiosis under varying energetic demands.

    

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5. Administration of FVIII-Expressing Human Placental Cells to Juvenile Sheep Yields Multi- Organ Engraftment, Therapeutic Plasma FVIII Levels and Alter Immune Signaling Pathways to Evade FVIII Inhibitor Induction

   Trevisan, Brady ; Rodriguez, Martin ; Dizon, Jacqueline ; George, Sunil ; Shields, Jordan ; Lankford, Shannon ; Combs, Rebessa ; Owen, John ; Atala, Anthony ; Doering, Christopher ; et al ( December 2021 , ASH)

   Administration of FVIII-Expressing Human Placental Cells to Juvenile Sheep Yields Multi-Organ Engraftment, Therapeutic Plasma FVIII Levels and Alter Immune Signaling Pathways to Evade FVIII Inhibitor Induction 63rd ASH Annual Meeting and Exposition, December 11-14, 2021, Georgia World Congress Center, Atlanta, GA Program: Oral and Poster Abstracts Session: 801. Gene Therapies: Poster III Hematology Disease Topics & Pathways: Bleeding and Clotting, Biological, Translational Research, Hemophilia, Genetic Disorders, Immune Mechanism, Diseases, Gene Therapy, Therapies, Adverse Events, Biological Processes, Transplantation Monday, December 13, 2021, 6:00 PM-8:00 PM We have previously reported that normal juvenile sheep that received weekly intravenous (IV) infusions of human (n=3) or an expression/secretion-optimized, bioengineered human/porcine hybrid (ET3) FVIII protein (n=3) for 5 weeks (20 IU/kg) developed anti-FVIII inhibitory antibodies (10-116 BU, and IgG titers of 1:20–1:245) by week 3 of infusion. By contrast, the IV infusion, or IP administration, of human placental mesenchymal cells (PLC) transduced with a lentiviral vector encoding a myeloid codon-optimized ET3 transgene (PLC-mcoET3) to produce high levels of ET3 protein (4.9-6IU/10^6 cells/24h) enabled the delivery of FVIII without eliciting antibodies, despite using PLC-mcoET3 doses that provided ~20-60 IU/kg ET3 each 24h to mirror the amount of FVIII protein infused. In addition, we showed that the route of PLC-mcoET3 administration (IP vs IV) did not impact the resultant plasma FVIII levels, with animals in these two groups exhibiting mean increases in FVIII activity (quantified by aPTT) of 30.9% and 34.2%, respectively, at week 15 post-treatment. Here, we investigated whether the sites and levels of PLC-mcoET3 engraftment were dependent upon the route of administration and performed s sheep-specific multiplexed transcriptomic analysis (NanoString) to define the immune signaling pathways that thwarted FVIII/ET3 protein immune response when ET3 was delivered through PLC. Tissue samples were collected from various organs at euthanasia and RT-qPCR performed using primers specific to the mcoET3 transgene, to the human housekeeping transcript GAPDH, and to sheep GAPDH, to quantify PLC-mcoET3 tissue engraftment, and normalize the results. RT-qPCR demonstrated PLC-mcoET3 engrafted, in both IP and IV groups, in all the organs evaluated (liver, lung, lymph nodes, thymus, and spleen). Animals that received PLC-mcoET3 via the IP route displayed higher overall levels of engraftment than their IV counterparts. The spleen was the preferential organ of engraftment for both IP and IV groups (IP:2.41±1.97%; IV: 0.64±0.54%). The IP group exhibited significantly higher engraftment in the left lobe of the liver (IP: 1.36±0.35%; IV: 0.041±0.022%), which was confirmed by immunohisto-chemistry (IHC) with an antibody to the human nuclear antigen Ku80 and ImageJ analysis (IP:5.24±3.36%; IV: 0±0). Of note is that the IP route resulted in higher levels of engraftment in the thymus, while IV infusion yielded higher levels of PLC-mcoET3 in lymph nodes. Analysis of H&E-stained tissues demonstrated they were devoid of any abnormal histologic changes and exhibited no evidence of hyperplasia or neoplasia, supporting the safety of the cell platform, irrespective of the route of administration. To date, NanoString analysis of PBMC collected at day 0, week 1, and week 5 post-infusion demonstrated that animals who received FVIII protein had upregulation of UBA5 and BATF, genes involved in antigen processing and Th17 signaling pathways, respectively. Although both IV and IP recipients of PLC-mcoET3 also had an increase in BATF, the IV group exhibited upregulation of BTLA, a gene involved in immune-tolerance, and downregulation of NOTCH and DDL1, involved in T cell differentiation, as well as MAPK12 and PLCG1, genes involved in proinflammatory cytokine regulation and T signaling within the Th17 signature. In IP recipients, BTLA, NOTCH, and DLL1 were all downregulated. Since ET3-reactive Th1 cells were not present in any of the treated animals, it is possible that the Th17 cells are responsible for the inhibitory antibodies seen in the juvenile sheep treated with FVIII/ET3 protein, while in animals receiving PLC-mcoET3, downregulation of genes involved in T cell differentiation and proinflammatory cytokine signaling keeps the immune system in check to avoid an immune response. Disclosures: Doering: Expression Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Spencer: Expression Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. 

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