Project description:High-throughput proteomics was used to determine the role of the fish liver in defense responses to bacterial infection, done using a rainbow trout (Oncorhynchus mykiss) model following infection with Aeromonas salmonicida, the causative agent of furunculosis. The vertebrate liver has multifaceted roles in innate immunity, metabolism, and growth; we hypothesize this tissue serves a dual function in supporting host defense in parallel to metabolic adjustments that promote effective immune function. While past studies have reported mRNA responses to A. salmonicida in salmonids, the impact of bacterial infectionon the liver proteome remains uncharacterized in fish.
Project description:The vertebrate kidneys play two evolutionary conserved roles in waste excretion and osmoregulation. Besides, the kidney of fish is considered as a functional ortholog of mammalian bone marrow that serves as a hematopoietic hub for generating blood cell lineages and immunological responses. However, knowledge about the properties of kidney hematopoietic cells, and the functionality of kidney in fish immune systems remain to be elucidated. To this end, our present study generated a comprehensive atlas with 59 hematopoietic stem/progenitor cell (HSPC) and immune-cell types from zebrafish kidney via single-cell transcriptome profiling analysis. These populations included almost all known cells associated with innate and adaptive immunity, and displayed differential responses to viral infection, indicating their diverse functional roles in antiviral immunity. Remarkably, HSPCs were found to have extensive reactivities to viral infection, and the trained immunity can be effectively induced in certain HSPCs. In addition, the antigen-stimulated adaptive immunity can be fully generated in kidney, suggesting kidney acting as a secondary lymphoid organ. These results indicated that fish kidney is a dual-functional entity with functionalities of both primary and secondary lymphoid organs. Our findings illustrated the unique features of fish immune system, and highlighted the multifaced biology of kidney in ancient vertebrates.
Project description:The paper describes a model on the key components for tumor–immune dynamics in multiple myeloma.
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This model is described in the article:
The Role of the Innate Immune System in Oncolytic Virotherapy
Tuan Anh Phan and Jianjun Paul Tian
Computational and Mathematical Methods in Medicine (2017) 6587258
Abstract:
The complexity of the immune responses is a major challenge in current virotherapy. This study incorporates the innate immune response into our basic model for virotherapy and investigates how the innate immunity affects the outcome of virotherapy. The viral therapeutic dynamics is largely determined by the viral burst size, relative innate immune killing rate, and relative innate immunity decay rate. The innate immunity may complicate virotherapy in the way of creating more equilibria when the viral burst size is not too big, while the dynamics is similar to the system without innate immunity when the viral burst size is big.
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Project description:Experimentally infected Atlantic salmon post-smolts exhibited different outcomes of disease (CMS). High responder (HR) fish were characterized with sustained and increased viral load and pathology in heart tissue. Low responder (LR) fish showed declining viral load from 6-10 weeks post infection (wpi) and absence of pathology. Global gene expression analyses were performed to compare these groups. Virus-responsive genes involved in early antiviral and innate immune responses were upregulated equally in LR and HR at the first stage (2-4 wpi), reflecting the initial increase in virus replication. Repression of heart muscle development indicated the early onset of pathology. By six weeks both responder groups had comparable viral loads, while increased pathology was observed in HR fish. This was reflected by induced expression of genes implicated in apoptosis and cell death, presumably related to lymphocyte regulation and survival. In contrast, LR fish showed earlier activation of NK cell-mediated cytotoxicity and NOD-like receptor signaling pathways. At the late stage of infection, increased pathology and viral load in HR was accompanied by a broad activation of genes involved in adaptive immunity and particularly T cell responses, probably reflecting the increased infiltration and homing of virus-specific T cells to the infected heart. This was in sharp contrast to LR fish, where recovery and reduced viral load was associated with a significantly reduced transcription of adaptive immunity genes and activation of genes involved in energy metabolism. Atlantic salmon post smolts (average weight 50g) were challenged with the putative CMS causing pathogen (PMCV). Heart was sampled from challenged and control fish at 2, 4, 6, 8 and 10 wpi. Heart pathology was detectable earliest at 6 wpi and from this time-point, individuals were assigned to HR and LR.
Project description:Vertebrates are protected from pathogens by an adaptive and an innate immune system. In mammals, loss of the adaptive immune system severely compromises viability. Zebrafish, in contrast, can survive for relatively long without adaptive immunity, as demonstrated by the immuno-deficient Rag1 mutant. Here, we examine whether the innate immune system is activated in the mutant, and ask whether this has any effect on the nervous system, given the finding that inflammation is linked to neurodegeneration in higher vertebrates. Using microarray analysis of the olfactory epithelium, we show that innate immune responses are upregulated. Neuronal genes are down-regulated, and immunofluorescence for the neural marker HuC shows a progressive loss of olfactory sensory neurons in mutants. Propodium iodide uptake indicates a corresponding increase in cell death. Rag1 mutant fish progressively lose their sensitivity to an olfactory cue, the alarm pheromone Schreckstoff, indicating that neuro-degeneration has a behavioral significance. Taken together, these data establish that immuno-deficiency in the zebrafish is accompanied by neuro-inflammation and loss of neurons. The microarray data document transcriptional changes associated with activation of innate immunity in the context of immunodeficiency and also identify novel genes that are potentially related to function of the olfactory system. Keywords: analysis of mutant A total of 6 RNA samples were used for hybridization. 3 were from the olfactory rosettes of wild type adult zebrafish and 3 were from Rag1 mutants.
Project description:Monocyte differentiation into macrophages represents one of the cornerstone processes in innate host defense. In addition, immunological imprinting of either tolerance or trained immunity after an initial infection determines the functional fate of innate immune cells and the susceptibility of the host to secondary infections. Here we comprehensively characterize the epigenetic profiles of these functional states relative to healthy adult naM-CM-/ve monocytes. Inflammatory and metabolic pathways are strongly modulated in the derived macrophages, including decreased activation of inflammasome components. The cAMP-dependent signaling pathway is remodeled and adrenergic signaling was functionally implicated in trained innate immunity induction in vivo. Interestingly, M-oM-^AM-"-Glucan trains innate immune cells through extensive remodeling of distal regulatory region-bound histone acetylation, resulting in a sizeable exclusive epigenomic signature. Accordingly, genome-wide transcription factor footprint analysis reveals a specific transcription factor repertoire at trained cell-specific enhancers when recouped with epigenetic data, forming a rich hypothesis generator to manipulate innate immunity. Monocytes were pre-incubated either with cell culture medium (RPMI), M-NM-2-glucan (5M-BM-5g/mL) or with LPS (100ng/mL), for 24 hours in a total volume of 10 mL. After a wash-out, cells were cultured in RPMI supplemented with 10% human pool serum. Monocytes were collected at different time points (0 h and 6 d after treatment) and counted before further treatment for chromatin immunoprecipitation, RNA or DNaseI treatment. Different donor Buffycoats (BC) were used as independent replicates. Replicates were generated for all the profiles including ChIPseq,RNAseq and DNaseIseq.
Project description:Adaptive immunity and the five vertebrate NF-kB/Rel family members first appeared in cartilaginous fish, suggesting that NF-kB family expansion allowed the acquisition of new functions to regulate adaptive immune responses. Transcriptome profiling revealed that, even in macrophages, the NF-kB family member, c-Rel, most potently regulates a cytokine gene linked to adaptive immunity, Il12b, with limiting roles at key regulators of innate immunity. Neofunctionalization of c-Rel to regulate Il12b depends on its unique DNA-binding properties, which we examined using structural, biochemical, functional, and genomic approaches. Among our findings was functional c-Rel homodimer binding to motifs with little resemblance to canonical NF-kB motifs. To determine whether c-Rel’s unique binding properties drove c-Rel-RelA divergence, we compared binding properties in various vertebrate species. c-Rel-RelA binding properties diverged in mammals and amphibians but were comparable in earlier vertebrates, suggesting that divergent DNA binding emerged relatively late during vertebrate evolution to support increasing complexity of adaptive immune regulation.
Project description:FT500 is an off-the-shelf, iPSC-derived NK cell product that can bridge innate and adaptive immunity, and has the potential to overcome multiple mechanisms of immune checkpoint inhibitor (ICI) resistance. The preclinical data provide compelling evidence supporting the clinical investigation of FT500 as monotherapy and in combination with ICI in participants with advanced solid tumors.