Inflammasome Signaling And Bacterial Infections

This volume details our current understanding of the architecture and signaling capabilities of known canonical and non-canonical inflammasome complexes and highlights their action, in particular in response to infection with important bacterial model organisms and the corresponding disease pathologies. The first chapters review new insights into the assembly and structures of inflammasome components and emphasize general strategies of up- and downstream signaling events. In addition, the authors specifically discuss the composition and activity of inflammasomes during infection with various gut pathogens (Salmonella, Shigella, Yersinia, Listeria and Helicobacter), respiratory pathogens (Mycobacterium, Legionella, Burkholderia and Streptococcus) as well as skin and soft tissue pathogens (Francisella and Staphylococcus). The discoveries presented provide a better understanding of the cellular and molecular biology of inflammasomes, which will pinpoint important new therapeutic targets for the treatment and prevention of multiple infectious diseases in the future. It is a valuable resource for students, scientists and clinicians, providing up-to-date information on this emerging research topic.

The inflammasome was first described in 2002 as a molecular complex activating proinflammatory caspases and therefore regulating the maturation and biological activities of cytokines such as IL-1 and IL-18. This finding was substantiated by the identification of several mutations in the cias1 gene, encoding the human NLRP3 protein, responsible for several autoinflammatory disorders such as the Muckle Wells syndrome. Since, the interest for this complex has constantly increased and several inflammasome complexes with different specificities have been described. These inflammasomes sense a wide variety of pathogens and danger signals and are key players in the inflammatory response. With the contributions of leading international experts in the field, this book provides an extensive overview of the current knowledge of inflammasome biology and their role in health and disease.

This Methods in Molecular Biology book offers methods for studying inflammasome function, including generation of inflammasome stimuli, monitoring of caspase-1 activity and processing, activation of IL-1β cytokines, plus lab protocols, material lists and tips.

Our gut is colonized by numerous bacteria throughout our life, and the gut epithelium is constantly exposed to foreign microbes and dietary antigens. Thus, the gut epithelium acts as a barrier against microbial invaders and is equipped with various innate defense systems. Resident commensal and foreign invading bacteria interact intimately with the gut epithelium and can impact host cellular and innate immune responses. From the perspective of many pathogenic bacteria, the gut epithelium serves as an infectious foothold and port of entry for disseminate into deeper tissues. In some instances when the intestinal defense activity and host immune system become compromised, even commensal and opportunistic pathogenic bacteria can cross the barrier and initiate local and systematic infectious diseases. Conversely, some highly pathogenic bacteria, such as those highlighted in this book, are able to colonize or invade the intestinal epithelium despite the gut barrier function is intact. Therefore, the relationship between the defensive activity of the intestinal epithelium against microbes and the pathogenesis of infective microbes becomes the basis for maintaining a healthy life. The authors offer an overview of the current topics related to major gastric and enteric pathogens, while highlighting their highly evolved host (human)-adapted infectious processes. Clearly, an in-depth study of bacterial infectious strategies, as well as the host cellular and immune responses, presented in each chapter of this book will provide further insight into the critical roles of the host innate and adaptive immune systems and their importance in determining the severity or completely preventing infectious diseases. Furthermore, under the continuous threat of emerging and re-emerging infectious diseases, the topic of gut-bacteria molecular interactions will provide various clues and ideas for the development of new therapeutic strategies.

Inflammasome Biology: Fundamentals, Role in Disease States, and Therapeutic Opportunities is a complete reference on the role of inflammasomes in health and disease. Sections cover the different types of inflammasomes, including cellular signaling, structural and evolutive aspects, overview the role of inflammasomes in key diseases, microbial infections and human body systems conditions, cover the interplay between Inflammasomes and cell death processes, and discuss current therapeutic opportunities driven by inflammasome research, including targeting, blocking and inhibiting the development of inflammasomes through both synthetic and natural compounds. This book is the perfect reference for cell biologists, immunologists and research clinicians to understand the foundations of inflammasomes and explore the therapeutic opportunities they present. Pharma researchers may also find this reference invaluable in devising new approaches to developing anti-inflammatory drugs. Provides comprehensive coverage of the subject of inflammasome biology Authored by leading experts worldwide Provides biological insights that have both health implications and therapeutic potential

Multicellular organisms are constantly exposed to microorganisms, such as viruses and bacteria, many of which are infectious pathogens. The immune system evolved to provide protection against these organisms, and includes numerous components to defend against a diverse, rapidly evolving pool of pathogens. The immune system is classically divided into two arms, the innate and adaptive systems. The time and metabolic cost of activating the T and B cell responses are considerable, and can also have deleterious side effects if the response is not properly controlled. Therefore, the adaptive immune system is carefully regulated so as to be activated only when necessary. The innate immune system serves to control most pathogens in a more rapid, less energetically expensive manner than the adaptive immune system, and to help regulate subsequent immune responses, guiding and controlling them in order to most efficiently clear pathogens with a minimum of pathological side effects. Among the first elements of the innate system that pathogens encounter are pattern recognition receptors, invariant receptors that detect conserved pathogen associated molecular patterns. Upon recognizing its binding ligand, a pattern recognition receptor will activate a signaling cascade that often triggers production and/or release of one or more pro- inflammatory cytokines. These in turn modulate additional elements of both the innate and adaptive immune responses, and are often critical lynchpins of host defense. Due to this central role in the immune system we investigated the roles of two distinct innate inflammatory pathways, the inflammasome and the MDA5-dependent portion of the type 1 interferon response, during infection with the murine coronavirus mouse hepatitis virus (MHV). Utilizing transgenic mice deficient in Caspase-1 and -11, which catalyze all inflammasome processing, the IL-1 receptor, the IL-18 receptor, or MDA5, we characterize the disease course and subsequent immune response following infection with MHV, a model murine coronavirus. We find that inflammasome signaling is protective during infection, and that much or all of this protection is mediated by IL-18 signaling driving production of interferon gamma by T cells. We also demonstrate that MDA5 signaling controls viral tropism and replication, and that in its absence the host immune response becomes over active, likely leading to lethal pathology. Overall, our studies help define how innate inflammatory pathways can have diverse influences on pathogenesis and the immune response.

DNA Sensors and Inflammasomes, Volume 625, the latest release in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. New sections in this release include Phosphorylation and dimerization of STING and IRF3, cGAS enzymology, Synthesis and identification of immuno-stimulatory CDNs, Tracking cGAS activity/ cGAMP formation using SPR/NMR, Using an enzyme coupled assay to track cGAS activity under steady states, Tracking the polymerization of DNA sensors, inflammasome receptors, and downstream signaling partners using FRET, NLRC4 structure, Tracking TREX1 activity, DNA association and dissociation kinetics of PARP1, and more.

Bacterial resistance to antibiotics is becoming a major threat to public health. It is imperative to find new therapeutic interventions to fight pathogens. Thus, deciphering host-pathogen interactions may allow defining targets for new strategies for effective treatments of infectious diseases. This chapter focuses on the bacterial manipulation of the host cell actin cytoskeleton. We discuss three infectious processes. The first is pathogen establishment of infection/invasion, explaining cellular uptake pathways that rely on actin, such as phagocytosis and macropinocytosis. The second process focus on the establishment of a replication niche, a process that subverts cytoskeletal functions associated with membrane trafficking namely phagosome maturation and cellular innate immune responses. Finally, pathogen dissemination is an emerging field that microfilaments have shown to participate: pathogen motility through the cytoplasm and from cell-to-cell or on the outer surface of the plasma membrane mimicking a receptor tyrosine kinase signaling pathway that helps the projection of pathogens to neighboring cells. It also establishes a connection with the innate immunity related with induction of cell signaling to inflammation, inflammasome activation, and programmed cell death. These studies revealed several potential targets related to actin cytoskeleton manipulation to design new therapeutic strategies for bacterial infections.

The cytoskeleton is a highly dynamic intracellular platform constituted by a three-dimensional network of proteins responsible for key cellular roles as structure and shape, cell growth and development, and offering to the cell with "motility" that being the ability of the entire cell to move and for material to be moved within the cell in a regulated fashion (vesicle trafficking). The present edition of Cytoskeleton provides new insights into the structure-functional features, dynamics, and cytoskeleton's relationship to diseases. The authors' contribution in this book will be of substantial importance to a wide audience such as clinicians, researches, educators, and students interested in getting updated knowledge about molecular basis of cytoskeleton, such as regulation of cell vital processes by actin-binding proteins as cell morphogenesis, motility, their implications in cell signaling, as well as strategies for clinical trial and alternative therapies based in multitargeting molecules to tackle diseases, that is, cancer.