Intracellular Signaling Networks In The Immune Response

Author : Andrew Neely Hotson
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (651 download)

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Download or read book Host Intracellular Signaling Networks are Perturbed During Bacterial Infection written by Andrew Neely Hotson and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The immune response to a pathogen is a complex interplay between host factors aimed to eradicate the pathogen, and microbe virulence proteins designed to subvert the host. To successfully combat a pathogen, the host must identify the insult and activate an immune response tailored to eliminate the specific microbe. This entails cell signaling at the level of innate immunity to detect the pathogen and mount an immediate non-specific response, while also communicating to bystander cells to shape the scope of the adaptive arm of immunity. The work herein investigates how the intracellular signaling network is activated and perturbed across cell types and hematopoietic tissues during bacterial infection. An introductory background on the current knowledge in the field of immune signaling is provided in chapter 1. Antigen presenting cells detect pathogenic motifs via pattern recognition receptors including toll-like receptors. This triggers an intracellular signaling cascade with specific transcriptional consequences, including the production of cytokines. In turn, these cytokines alert additional cell types to activate specific signal transducer and activator of transcription (STAT) transcription factor family members. Thus, detection of a microbe initiates rapid signaling across leukocytes to set the stage for the immune response. Chapter 2 focuses on cell signaling experiments in a murine model for the onset of sepsis. Mice were acutely challenged with avirulent E. coli and Listeria monocytogenes to study the host response without pathogenic manipulation of host signaling by bacterial virulence factors. Bacterial challenge causes macrophages and dendritic cells to become attenuated in their ability to respond to TLR agonists, a hallmark of endotoxin tolerance. Also, it induces global dampening of the STAT response to cytokines across all cell types; splenocytes from challenged mice poorly respond to cytokine stimulation. Cytokines secreted by antigen presenting cells act on bystander cells and induced negative feedback, including SOCS expression and receptor endocytosis that prevent further STAT activation. Thus, bacterial recognition causes host immune activation followed by subsequent suppression of signaling. The work in chapter 3 transitions to a model of chronic infection with pathogenic Salmonella typhimurium. In addition to examining the innate response, this model enables investigation of adaptive immunity by monitoring the activation of T cells, their cytokine response profile, and TH-biasing by the transcription factors they express and cytokines they produce. During chronic infection, B cells and effector T cells undergo expansion but not contraction over the first 30 days, demonstrating that the immune system establishes a new equilibrium. However, the degree of cell expansion, as well as the ability of these cells to respond to cytokine, is quite variable across mice. These mice also have varied levels of bacterial burden, and the shape of the immune response denotes disease severity. High bacterial load is associated with trademarks of innate immunity such as elevated neutrophil numbers, serum cytokine levels, and the dampened STAT signaling observed during bacterial challenge in chapter 2. In contrast, the mice that control infection are enriched for markers of adaptive T cell immunity: high numbers of TH1 effector T cells, T cell proliferation, ability to respond to cytokines, and fewer regulatory T cells. Therefore, a strong adaptive response is correlated with containing the infection, while an innate response is indicative of high bacterial levels. This thesis concludes in chapter 4, with a discussion of how the findings fit in the context of cell signaling in other disease states. Leukemia and lymphomas, diseases of uncontained cell growth, are characterized by hyperactive cell signaling. In contrast, an activated immune response, such as during auto-immunity or in cancer infiltrating T cells, is marked by repressed ability to respond to cytokines. As inhibited cytokine responses were also observed during bacterial challenge and during severe chronic infection, it appears that a commonality amongst disease that activate an immune response is negative feedback to dampen further signaling and restrict inflammation.