Cold-blooded vertebrate utilizes behavioral fever to alleviate T-cell apoptosis and optimize antimicrobial immunity
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ABSTRACT: Fever confers significant survival benefits on endotherms by optimizing both innate and adaptive immunity. Ectotherms achieve thermoregulation using behavioral strategies, but existing evidence supports its enhancement effect on innate immunity only. Therefore, it remains unknown whether the coordination between fever and adaptive immunity was independently acquired by endotherms or instead represents a gradually evolved function common to vertebrates. In the present study, we reported that Nile tilapia developed behavioral fever to enhance the immune response against Edwardsiella piscicida infection. Behavioral fever lasted five days, and the immune potential was optimized at 4–6 days post infection, indicating a potential correlation between fever events and T-cell immunity. Further investigation suggested that fever did not affect T-cell activation or proliferation but improved the ability of T cells to produce IFN- and Granzyme B and enhanced cytotoxicity, thereby eliminating the infection more effectively. Notably, we identified a previously unknown advantage conferred by fever during infection: alleviation of T-cell apoptosis to maintain a considerable T-cell pool. Mechanistically, fever induced the expression of HSP70, which in turn entered the nucleus and bound to and promoted the phosphorylation of ERK1/2, thereby inhibiting the cleavage of caspase-8/caspase-3 and preventing T-cell apoptosis. Our findings elucidate the detailed mechanism by which behavioral fever optimizes T-cell immunity in a cold-blooded vertebrate and propose that integrating fever with adaptive immunity to gain survival advantages is an ancient strategy acquired before the emergence of tetrapod.
Project description:The adaptor protein ASC contributes to innate immunity through the assembly of caspase-1-activating inflammasome complexes. We demonstrate that ASC plays an inflammasome-independent cell-intrinsic role in adaptive immune cells. Asc-/- mice displayed defective antigen presentation by dendritic cells and lymphocyte migration due to impaired Rac-mediated actin polymerization. Genome-wide analysis showed that ASC, but not Nlrp3 or caspase-1, controls mRNA stability and expression of DOCK2, a guanine nucleotide exchange factor that mediates Rac-dependent signaling in immune cells. DOCK2-deficient dendritic cells showed similar defective antigen uptake as Asc-/- cells. Ectopic expression of DOCK2 in ASC-deficient cells restored Rac-mediated actin polymerization, antigen uptake and chemotaxis. Thus, ASC shapes adaptive immunity independently of inflammasomes by modulating DOCK2-dependent Rac activation and F-actin polymerization in dendritic cells and lymphocytes. Three replicates of naïve WT and three replicates of Asc-/- bone marrow derived dendritic cells were analyzed on the Affymetrix HT MG-430 PM plate array.
Project description:Edwardsiella tarda is a Gram-negative bacterial pathogen that can infect a wide range of freshwater and marine fish. However, the immune evasion mechanisms of Edwardsiella tarda is not fully understood. We found that Edwardsiella tarda infection generally significantly upregulated and downregulated a lot of immune-related genes of zebrafish ZF4 cells using RNA-seq technology.
Project description:This SuperSeries is composed of the following subset Series: GSE28481: Transcriptome analysis of the zebrafish embryonic host response to Edwardsiella tarda infection using a static immersion systems [experiment A] GSE28485: Transcriptome analysis of the zebrafish embryonic host response to Edwardsiella tarda infection [experiment B] Refer to individual Series
Project description:The adaptor protein ASC contributes to innate immunity through the assembly of caspase-1-activating inflammasome complexes. We demonstrate that ASC plays an inflammasome-independent cell-intrinsic role in adaptive immune cells. Asc-/- mice displayed defective antigen presentation by dendritic cells and lymphocyte migration due to impaired Rac-mediated actin polymerization. Genome-wide analysis showed that ASC, but not Nlrp3 or caspase-1, controls mRNA stability and expression of DOCK2, a guanine nucleotide exchange factor that mediates Rac-dependent signaling in immune cells. DOCK2-deficient dendritic cells showed similar defective antigen uptake as Asc-/- cells. Ectopic expression of DOCK2 in ASC-deficient cells restored Rac-mediated actin polymerization, antigen uptake and chemotaxis. Thus, ASC shapes adaptive immunity independently of inflammasomes by modulating DOCK2-dependent Rac activation and F-actin polymerization in dendritic cells and lymphocytes.
Project description:Transcriptional profiling of the zebrafish embryonic host response to infection by injection of 200 CFUs of Edwardsiella tarda (strain FL6-60)
Project description:Baris Hancioglu, David Swigon & Gilles Clermont. A dynamical model of human immune response to influenza A virus infection. Journal of Theoretical Biology 246, 1 (2007).
We present a simplified dynamical model of immune response to uncomplicated influenza A virus (IAV) infection, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells (cytotoxic T-cells and natural killer cells). Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov and Romanyukha [1994. Mathematical model of antiviral immune response. III. Influenza A virus infection. J. Theor. Biol. 167, 323-360], the model is constructed as a system of 10 ordinary differential equations with 27 parameters characterizing the rates of various processes contributing to the course of disease. The parameters are derived from published experimental data or estimated so as to reproduce available data about the time course of IAV infection in a naïve host. We explore the effect of initial viral load on the severity and duration of the disease, construct a phase diagram that sheds insight into the dynamics of the disease, and perform sensitivity analysis on the model parameters to explore which ones influence the most the onset, duration and severity of infection. To account for the variability and speed of adaptation of the adaptive response to a particular virus strain, we introduce a variable that quantifies the antigenic compatibility between the virus and the antibodies currently produced by the organism. We find that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load.
Project description:Purpose: This goal of this study was to explore the host transcriptomic responses in African swine fever virus experimentally infected pigs using RNA-Sequencing. Methods: RNAs acquired from ten different organ tissue samples were sequenced. Sequencing reads were preprocessed, aligned with the reference genome, assembled and expressions were estimated through bioinformatics approaches. Result: Several uprugulated DEGs were identified. Conclusion: We found important candidate genes and pathways for further testing in African swine fever virus infection in pig.
Project description:Gene expression profiles by microarray have contributed for a elucidation of an immune-response and a determination of efficiency in vaccination. Recent day, edwardsielosis have caused a fatal damage in the aquaculture of Japanese flounder, Paralichthys olivaceus. However the formalin killed-cell vaccines made from Edwardsiella tarda isolated same fish species were not efficient. Recent our study revealed the mixed FKC vaccine made from the two different type of E. tarda protected Japanese flounder against Edwardsiella tarda infection for long-term. In this study, we analyzed the immune-response of a vaccinated fish kidney using the mixed FKC vaccine against Edwardsiella tarda with an Agilent custom-oligo DNA microarray on 9,573 probes of Japanese flounder. Our study revealed that the mixed FKC vaccine confered a strong immune-response and keeped a efficient for long-term on Japanese flounder.
Project description:Different types of cell death, including apoptosis, play an important role in the immune defense of arthropods, as infected cells are eliminated, preventing the dissemination of the infectious agent throughout the animal body. The apoptosis can be triggered by two main pathways: the intrinsic or mitochondrial pathway and the extrinsic or death receptor pathway. Both culminate in the activation of the effector caspases, such as caspase-3, resulting, for instance in DNA fragmentation and exposition of markers on the surface of the apoptotic cell, allowing its recognition and elimination by phagocytic cells. To ensure survival and proliferation, microorganisms can inhibit apoptosis of the host cell. The differential proteome of a tick cell line (BME26) in response to an experimental infection with Rickettsia rickettsii, causative agent of the severe Rocky Mountain spotted fever, showed that pro-apoptotic proteins are downregulated in the beginning of infection (6 h) and upregulated in a later time-point (48 h). We therefore evaluated the effects of infection on classic features of apoptotic cells: the spontaneous fragmentation of gDNA and the activity of caspase-3 and the exposition of phosphatidylserine in BME26 cells after induction with staurosporine, a classic activator of apoptosis. The spontaneous fragmentation of DNA was observed exclusively in non-infected cells. In addition, the activity of caspase-3 and the exposition of phosphatidylserine is lower in infected than in non-infected cells. Caspase-3 activity is also lower in infected IBU/ASE-16 cells, an embryonic tick cell line of one primary vector of R. rickettsii in Brazil, Amblyomma sculptum. Importantly, while the activation of caspase-3 exerted a detrimental effect on rickettsial proliferation in BME26 cells, the enzyme inhibition increased bacterial growth. Together, our results suggest that R. rickettsii controls the apoptosis in tick cells, which seems to be important to ensure the colonization of the vector cell. To the best of our knowledge, this is the first report on the modulation of the apoptosis in a tick cell line upon the infection with a species of the genus Rickettsia.