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1. Expression of Human Endogenous Retroviruses in Systemic Lupus Erythematosus: Multiomic Integration With Gene Expression

   https://doi.org/10.3389/fimmu.2021.661437  

   Stearrett, Nathaniel; Dawson, Tyson; Rahnavard, Ali; Bachali, Prathyusha; Bendall, Matthew L.; Zeng, Chen; Caricchio, Roberto; Pérez-Losada, Marcos; Grammer, Amrie C.; Lipsky, Peter E.; et al (April 2021, Frontiers in Immunology)

   Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies predominantly to nuclear material. Many aspects of disease pathology are mediated by the deposition of nucleic acid containing immune complexes, which also induce the type 1interferon response, a characteristic feature of SLE. Notably, SLE is remarkably heterogeneous, with a variety of organs involved in different individuals, who also show variation in disease severity related to their ancestries. Here, we probed one potential contribution to disease heterogeneity as well as a possible source of immunoreactive nucleic acids by exploring the expression of human endogenous retroviruses (HERVs). We investigated the expression of HERVs in SLE and their potential relationship to SLE features and the expression of biochemical pathways, including the interferon gene signature (IGS). Towards this goal, we analyzed available and new RNA-Seq data from two independent whole blood studies using Telescope. We identified 481 locus specific HERV encoding regions that are differentially expressed between case and control individuals with only 14% overlap of differentially expressed HERVs between these two datasets. We identified significant differences between differentially expressed HERVs and non-differentially expressed HERVs between the two datasets. We also characterized the host differentially expressed genes and tested their association with the differentially expressed HERVs. We found that differentially expressed HERVs were significantly more physically proximal to host differentially expressed genes than non-differentially expressed HERVs. Finally, we capitalized on locus specific resolution of HERV mapping to identify key molecular pathways impacted by differential HERV expression in people with SLE. 

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2. 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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3. Spatial variation in gene expression of Tasmanian devil facial tumors despite minimal host transcriptomic response to infection

   https://doi.org/10.1186/s12864-021-07994-4  

   Kozakiewicz, Christopher P.; Fraik, Alexandra K.; Patton, Austin H.; Ruiz-Aravena, Manuel; Hamilton, David G.; Hamede, Rodrigo; McCallum, Hamish; Hohenlohe, Paul A.; Margres, Mark J.; Jones, Menna E.; et al (December 2021, BMC Genomics)

   Abstract Background Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown. Results We sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation. Conclusions Expression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival. 

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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. Machine learning‐based identification of general transcriptional predictors for plant disease

   https://doi.org/10.1111/nph.20264  

   Sia, Jayson; Zhang, Wei; Cheng, Mingxi; Bogdan, Paul; Cook, David E (January 2025, New Phytologist)

   This study investigated the generalizability of Arabidopsis thaliana immune responses across diverse pathogens, including Botrytis cinerea, Sclerotinia sclerotiorum, and Pseudomonas syringae, using a data-driven, machine learning approach. Machine learning models were trained to predict disease development from early transcriptional responses. Feature selection techniques based on network science and topology were used to train models employing only a fraction of the transcriptome. Machine learning models trained on one pathosystem where then validated by predicting disease development in new pathosystems. The identified feature selection gene sets were enriched for pathways related to biotic, abiotic, and stress responses, though the specific genes involved differed between feature sets. This suggests common immune responses to diverse pathogens that operate via different gene sets.The study demonstrates that machine learning can uncover both established and novel components of the plant's immune response, offering insights into disease resistance mechanisms. These predictive models highlight the potential to advance our understanding of multigenic outcomes in plant immunity and can be further refined for applications in disease prediction. 

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