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Gautam B Awatramani - One of the best experts on this subject based on the ideXlab platform.
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intrinsic oscillatory activity arising within the electrically coupled aii amacrine on cone bipolar Cell Network is driven by voltage gated na channels
The Journal of Physiology, 2012Co-Authors: Stuart Trenholm, Joanna Borowska, Jiawei Zhang, Alex Hoggarth, Kyle Johnson, Steven Barnes, Timothy J Lewis, Gautam B AwatramaniAbstract:Key points • In mouse models for retinal degeneration, photoreceptor death leads to membrane oscillation in the remnant AII amacrine–ON cone bipolar Cell Network through an unknown mechanism. • We found such oscillations require voltage-gated Na+ channels and gap junctions but not hyperpolarization-activated currents (Ih). • Na+ channels are expressed predominantly in AII amacrine Cells and Ih in ON cone bipolar Cells, and appear to interact via gap junctions to shape oscillations. • Similar intrinsic oscillations arose in the wild-type (wt) AII amacrine–ON cone bipolar Cell Network when photoreceptor inputs to bipolar Cells were pharmacologically occluded. • Computational modelling captures experimental findings when a low level of Cellular heterogeneity is introduced in the coupled Network. • These unique insights into the Cellular mechanisms underlying spontaneous activity in the degenerating retina might aid in designing the most effective strategies to restore vision using retinal prosthesis. Abstract In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10–20 Hz) within the remnant electrically coupled Network of retinal ON cone bipolar and AII amacrine Cells. We tested the role of hyperpolarization-activated currents (Ih), voltage-gated Na+ channels and gap junctions in mediating such oscillatory activity. Blocking Ih (1 mm Cs+) hyperpolarized the Network and augmented activity, while antagonizing voltage-dependent Na+ channels (1 μm TTX) abolished oscillatory activity in the AII amacrine–ON cone bipolar Cell Network. Voltage-gated Na+ channels were only observed in AII amacrine Cells, implicating these Cells as major drivers of activity. Pharmacologically uncoupling the Network (200 μm meclofenamic acid (MFA)) blocked oscillations in all Cells indicating that Na+ channels exert their influence over multiple Cell types within the Network. In wt retina, occluding photoreceptor inputs to bipolar Cells (10 μm NBQX and 50 μm l-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine–ON cone bipolar Cell Network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced Network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na+ channel-dependent Network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na+ channels in AII amacrine Cells trigger degeneration-induced Network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.
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intrinsic oscillatory activity arising within the electrically coupled aii amacrine on cone bipolar Cell Network is driven by voltage gated na channels
The Journal of Physiology, 2012Co-Authors: Stuart Trenholm, Joanna Borowska, Jiawei Zhang, Alex Hoggarth, Kyle Johnson, Steven Barnes, Timothy J Lewis, Gautam B AwatramaniAbstract:In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10–20 Hz) within the remnant electrically coupled Network of retinal ON cone bipolar and AII amacrine Cells. We tested the role of hyperpolarization-activated currents (I(h)), voltage-gated Na(+) channels and gap junctions in mediating such oscillatory activity. Blocking I(h) (1 mm Cs(+)) hyperpolarized the Network and augmented activity, while antagonizing voltage-dependent Na(+) channels (1 μm TTX) abolished oscillatory activity in the AII amacrine-ON cone bipolar Cell Network. Voltage-gated Na(+) channels were only observed in AII amacrine Cells, implicating these Cells as major drivers of activity. Pharmacologically uncoupling the Network (200 μm meclofenamic acid (MFA)) blocked oscillations in all Cells indicating that Na(+) channels exert their influence over multiple Cell types within the Network. In wt retina, occluding photoreceptor inputs to bipolar Cells (10 μm NBQX and 50 μm l-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine-ON cone bipolar Cell Network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced Network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na(+) channel-dependent Network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na(+) channels in AII amacrine Cells trigger degeneration-induced Network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.
Alessandra Cesano - One of the best experts on this subject based on the ideXlab platform.
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immune monitoring technology primer single Cell Network profiling scnp
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Rachael E. Hawtin, Alessandra CesanoAbstract:Description of the technology Understanding a patients’ immune status not only from immune Cell phenotyping, but also through analysis of functional signaling capacity, enables the generation of a more comprehensive understanding of the complex mechanisms responsible for immunological tolerance in cancer, and generates data that is complementary to other non-functional phenotypic data sets such as immunohistochemical profiling and genomic analyses. Single Cell Network profiling (SCNP) is a technology that quantifies functional immune signaling capacity and connectivity at a systems biology level. The technology is based on multiparametric flow cytometry that simultaneously quantifies in multiple and rare immune Cell subsets, without the need for physical separation, both extraCellular surface markers and changes in intraCellular signaling proteins in response to extraCellular modulators. Quantifying modulated signaling across a panel of modulators (e.g., IFNα, IFNγ, IL-4, IL-10, IL-27, antiCD3 etc.) and intraCellular signaling pathways identifies the functional capacity of the signaling Network which cannot be assessed by measuring basal (unmodulated) signaling alone. A signaling node is defined as the combination of the extraCellular modulator with the intraCellular readout. For example TLR4 - > p-Erk defines one signaling node in which TLR4 modulation is quantified through the increase in p-Erk levels as compared to the unmodulated reference. Typically 3 nodes are captured simultaneously per well across multiple immune Cell subsets of interest (e.g., TLR4 - > p-Erk, p-S6, IkB). The application of SCNP to clinical decision-making requires the generation of high-content SCNP assays with robust, accurate, quantifiable and reproducible results across time, operators and instruments. Each of the procedural steps associated with an SCNP assay, including pre-analytical sample handling, assay execution and reagents, data acquisition and analysis and the generation of metrics, have been validated [1] (Figs. 1 and 2). Experimental assay setup is performed using proprietary software which enables experimental design/96well plate layouts and data capture to be contiguously linked, ensuring that data from each well is correctly assigned. The laboratory execution can be performed on as many as 30 samples assayed for up to 40 wells (approximately 200–500 SCNP dimensions comprising modulator/ inhibitor/intraCellular readout/Cell subset combinations) in 2 to 3 days depending on the kinetic time points. A statistical analysis plan (SAP) is drafted for all studies beyond the exploratory phase, based upon clearly stated objectives. For the identification of clinically validated classifiers the time frame for assay development and validation is comparable to that of other technologies (e.g., genomics, IHC) due to the requirements for statistical powering and for verification and validation in independent sample sets.
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single Cell Network profiling of peripheral blood mononuclear Cells from healthy donors reveals age and race associated differences in immune signaling pathway activation
Journal of Immunology, 2012Co-Authors: Diane M Longo, Rachael E. Hawtin, Santosh Putta, Erik Evensen, Brent Louie, Jason Ptacek, James Cordeiro, Ena Wang, Francesco M Marincola, Alessandra CesanoAbstract:A greater understanding of the function of the human immune system at the single-Cell level in healthy individuals is critical for discerning aberrant Cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune Cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune Cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-Cell Network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple Cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete Cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune Cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics.
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functional characterization of flt3 receptor signaling deregulation in acute myeloid leukemia by single Cell Network profiling scnp
PLOS ONE, 2010Co-Authors: David B Rosen, Steven M Kornblau, Mark D Minden, Santosh Putta, Aileen Cohen, Wendy J Fantl, Urte Gayko, John Woronicz, Erik Evensen, Alessandra CesanoAbstract:Background Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in Cellular responsiveness to signaling modulation may be more informative. Methodology/Principal Findings Using single Cell Network profiling (SCNP), Cells were treated with extraCellular modulators and their functional responses were quantified by multiparametric flow cytometry. IntraCellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and provide additional information for disease characterization and management. Conclusions/Significance These studies show the feasibility of SCNP to assess modulated intraCellular signaling pathways and characterize the biology of individual AML samples in the context of genetic alterations.
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dynamic single Cell Network profiles in acute myelogenous leukemia are associated with patient response to standard induction therapy
Clinical Cancer Research, 2010Co-Authors: Steven M Kornblau, Mark D Minden, David B Rosen, Santosh Putta, Aileen Cohen, Todd Covey, David C Spellmeyer, Wendy J Fantl, Urte Gayko, Alessandra CesanoAbstract:Purpose: Complete response to induction chemotherapy is observed in ∼60% of patients with newly diagnosed non-M3 acute myelogenous leukemia (AML). However, no methods exist to predict with high accuracy at the individual patient level the response to standard AML induction therapy. Experimental Design: We applied single-Cell Network profiling (SCNP) using flow cytometry, a tool that allows a comprehensive functional assessment of intraCellular signaling pathways in heterogeneous tissues, to two training cohorts of AML samples ( n = 34 and 88) to predict the likelihood of response to induction chemotherapy. Results: In the first study, univariate analysis identified multiple signaling “nodes” (readouts of modulated intraCellular signaling proteins) that correlated with response (i.e., AUC ROC ≥ 0.66; P ≤ 0.05) at a level greater than age. After accounting for age, similar findings were observed in the second study. For patients Conclusions: These data emphasize the value of performing quantitative SCNP under modulated conditions as a basis for the development of tests highly predictive for response to induction chemotherapy. SCNP provides information distinct from other known prognostic factors such as age, secondary AML, cytogenetics, and molecular alterations and is potentially combinable with the latter to improve clinical decision making. Independent validation studies are warranted. Clin Cancer Res; 16(14); 3721–33. ©2010 AACR.
Julian Cheng - One of the best experts on this subject based on the ideXlab platform.
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sensing time optimization and power control for energy efficient cognitive small Cell with imperfect hybrid spectrum sensing
IEEE Transactions on Wireless Communications, 2017Co-Authors: Haijun Zhang, Julian Cheng, Victor C. M. Leung, Arumugam NallanathanAbstract:Cognitive radio enabled small Cell Network is an emerging technology to address the exponential increase of mobile traffic demand in next generation mobile communications. Recently, many technological issues, such as resource allocation and interference mitigation pertaining to cognitive small Cell Network have been studied, but most studies focus on maximizing spectral efficiency. Different from the existing works, we investigate the power control and sensing time optimization problem in a cognitive small Cell Network, where the cross-tier interference mitigation, imperfect hybrid spectrum sensing, and energy efficiency are considered. The optimization of energy efficient sensing time and power allocation is formulated as a non-convex optimization problem. We solve the proposed problem in an asymptotically optimal manner. An iterative power control algorithm and a near optimal sensing time scheme are developed by considering imperfect hybrid spectrum sensing, cross-tier interference mitigation, minimum data rate requirement, and energy efficiency. Simulation results are presented to verify the effectiveness of the proposed algorithms for energy efficient resource allocation in the cognitive small Cell Network.
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cooperative interference mitigation and handover management for heterogeneous cloud small Cell Networks
IEEE Wireless Communications, 2015Co-Authors: Haijun Zhang, Chunxiao Jiang, Julian ChengAbstract:Heterogeneous small Cell Networks have attracted much attention for satisfying users’ explosive data traffic requirements. The heterogeneous cloud small Cell Network (HCSNet), which combines cloud computing and a heterogeneous small Cell Network, will likely play an important role in 5G mobile communication Networks. However, with massive deployment of small Cells, co-channel interference and handover management are two important problems in an HCSNet, especially for Cell edge users. In this article, we examine the problems of cooperative interference mitigation and handover management in an HCSNet. A Network architecture is described to combine cloud radio access Network with small Cells. An effective CoMP clustering scheme using affinity propagation is adopted to mitigate Cell edge users’ interference. A low-complexity handover management scheme is presented, and its signaling procedure is analyzed in an HCSNet. Numerical results show that with the proposed Network architecture, CoMP clustering and handover management schemes can significantly increase the capacity of HCSNet while maintaining users’ quality of service.
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Cooperative interference mitigation and handover management for heterogeneous cloud small Cell Networks
IEEE Wireless Communications, 2015Co-Authors: Julian Cheng, Victor C. M. LeungAbstract:Heterogeneous small Cell Network has attracted much attention to satisfy users' explosive data traffic requirements. Heterogeneous cloud small Cell Network (HCSNet), which combines cloud computing and heterogeneous small Cell Network, will likely play an important role in 5G mobile communication Networks. However, with massive deployment of small Cells, co-channel interference and handover management are two important problems in HCSNet, especially for Cell edge users. In this article, we examine the problems of cooperative interference mitigation and handover management in HCSNet. A Network architecture is described to combine cloud radio access Network with small Cells. An effective coordinated multi-point (CoMP) clustering scheme using affinity propagation is adopted to mitigate Cell edge users' interference. A low complexity handover management scheme is presented, and its signaling procedure is analyzed in HCSNet. Numerical results show that the proposed Network architecture, CoMP clustering scheme and handover management scheme can significantly increase the capacity of HCSNet while maintaining users' quality of service.
Stuart Trenholm - One of the best experts on this subject based on the ideXlab platform.
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intrinsic oscillatory activity arising within the electrically coupled aii amacrine on cone bipolar Cell Network is driven by voltage gated na channels
The Journal of Physiology, 2012Co-Authors: Stuart Trenholm, Joanna Borowska, Jiawei Zhang, Alex Hoggarth, Kyle Johnson, Steven Barnes, Timothy J Lewis, Gautam B AwatramaniAbstract:Key points • In mouse models for retinal degeneration, photoreceptor death leads to membrane oscillation in the remnant AII amacrine–ON cone bipolar Cell Network through an unknown mechanism. • We found such oscillations require voltage-gated Na+ channels and gap junctions but not hyperpolarization-activated currents (Ih). • Na+ channels are expressed predominantly in AII amacrine Cells and Ih in ON cone bipolar Cells, and appear to interact via gap junctions to shape oscillations. • Similar intrinsic oscillations arose in the wild-type (wt) AII amacrine–ON cone bipolar Cell Network when photoreceptor inputs to bipolar Cells were pharmacologically occluded. • Computational modelling captures experimental findings when a low level of Cellular heterogeneity is introduced in the coupled Network. • These unique insights into the Cellular mechanisms underlying spontaneous activity in the degenerating retina might aid in designing the most effective strategies to restore vision using retinal prosthesis. Abstract In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10–20 Hz) within the remnant electrically coupled Network of retinal ON cone bipolar and AII amacrine Cells. We tested the role of hyperpolarization-activated currents (Ih), voltage-gated Na+ channels and gap junctions in mediating such oscillatory activity. Blocking Ih (1 mm Cs+) hyperpolarized the Network and augmented activity, while antagonizing voltage-dependent Na+ channels (1 μm TTX) abolished oscillatory activity in the AII amacrine–ON cone bipolar Cell Network. Voltage-gated Na+ channels were only observed in AII amacrine Cells, implicating these Cells as major drivers of activity. Pharmacologically uncoupling the Network (200 μm meclofenamic acid (MFA)) blocked oscillations in all Cells indicating that Na+ channels exert their influence over multiple Cell types within the Network. In wt retina, occluding photoreceptor inputs to bipolar Cells (10 μm NBQX and 50 μm l-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine–ON cone bipolar Cell Network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced Network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na+ channel-dependent Network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na+ channels in AII amacrine Cells trigger degeneration-induced Network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.
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intrinsic oscillatory activity arising within the electrically coupled aii amacrine on cone bipolar Cell Network is driven by voltage gated na channels
The Journal of Physiology, 2012Co-Authors: Stuart Trenholm, Joanna Borowska, Jiawei Zhang, Alex Hoggarth, Kyle Johnson, Steven Barnes, Timothy J Lewis, Gautam B AwatramaniAbstract:In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10–20 Hz) within the remnant electrically coupled Network of retinal ON cone bipolar and AII amacrine Cells. We tested the role of hyperpolarization-activated currents (I(h)), voltage-gated Na(+) channels and gap junctions in mediating such oscillatory activity. Blocking I(h) (1 mm Cs(+)) hyperpolarized the Network and augmented activity, while antagonizing voltage-dependent Na(+) channels (1 μm TTX) abolished oscillatory activity in the AII amacrine-ON cone bipolar Cell Network. Voltage-gated Na(+) channels were only observed in AII amacrine Cells, implicating these Cells as major drivers of activity. Pharmacologically uncoupling the Network (200 μm meclofenamic acid (MFA)) blocked oscillations in all Cells indicating that Na(+) channels exert their influence over multiple Cell types within the Network. In wt retina, occluding photoreceptor inputs to bipolar Cells (10 μm NBQX and 50 μm l-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine-ON cone bipolar Cell Network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced Network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na(+) channel-dependent Network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na(+) channels in AII amacrine Cells trigger degeneration-induced Network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.
David Elashoff - One of the best experts on this subject based on the ideXlab platform.
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mycobacterium tuberculosis transfer rna induces il 12p70 via synergistic activation of pattern recognition receptors within a Cell Network
Journal of Immunology, 2018Co-Authors: Caroline Keegan, Stephan R Krutzik, Mirjam Schenk, Phillip Scumpia, Yan Ling Joy Pang, Brandon S Russell, Kok Seong Lim, Scarlet S Shell, Erin G Prestwich, David ElashoffAbstract:Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a Cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T Cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune Network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intraCellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK Cells to respond to IL-18 and produce IFN-γ, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene Network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct Cell types to induce IL-12p70.
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transfer rna induces il 12p70 via synergistic activation of pattern recognition receptors within a Cell Network
Journal of Immunology, 2018Co-Authors: Caroline Keegan, Stephan R Krutzik, Mirjam Schenk, Phillip Scumpia, Yan Ling Joy Pang, Brandon S Russell, Kok Seong Lim, Scarlet S Shell, Erin G Prestwich, David ElashoffAbstract:Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a Cell-mediated immune response against the foreign invader. The culture filtrate of contains ligands, such as tRNA, that activate the innate immune response and secreted Ags recognized by T Cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune Network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intraCellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK Cells to respond to IL-18 and produce IFN-γ, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that tRNA activates a gene Network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct Cell types to induce IL-12p70.