The microbiome and innate immunity Thaiss, Christoph A; Zmora, Niv; Levy, Maayan ...
Nature (London),
07/2016, Letnik:
535, Številka:
7610
Journal Article
Recenzirano
The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. ...The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host-microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.
The study of innate immunity and its link to inflammation and host defense encompasses diverse areas of biology, ranging from genetics and biophysics to signal transduction and physiology. Central to ...our understanding of these events are the Toll-like receptors (TLRs), an evolutionarily ancient family of pattern recognition receptors. Herein, we describe the mechanisms and consequences of TLR-mediated signal transduction with a focus on themes identified in the TLR pathways that also explain the operation of other immune signaling pathways. These themes include the detection of conserved microbial structures to identify infectious agents and the use of supramolecular organizing centers (SMOCs) as signaling organelles that ensure digital cellular responses. Further themes include mechanisms of inducible gene expression, the coordination of gene regulation and metabolism, and the influence of these activities on adaptive immunity. Studies in these areas have informed the development of next-generation therapeutics, thus ensuring a bright future for research in this area.
Kagan and Fitzgerald comprehensively review the functions and mechanisms of Toll-like receptors (TLRs), which are crucial detectors of microbial biomolecules and mediators of cellular immunity. They synthesize the overarching themes that have emerged from TLR signaling but are repeated throughout the pattern recognition receptor (PRR) superfamily.
Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, ...an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been ...termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.
Histone posttranslational modifications control eukaryotic gene expression and regulate many biological processes including immunity. Pathogens alter host epigenetic control to aid pathogenesis. We ...find that the intracellular bacterial pathogen Legionella pneumophila uses a Dot/Icm type IV secreted effector, RomA, to uniquely modify the host chromatin landscape. RomA, a SET domain-containing methyltransferase, trimethylates K14 of histone H3, a histone mark not previously described in mammals. RomA localizes to the infected cell nucleus where it promotes a burst of H3K14 methylation and consequently decreases H3K14 acetylation, an activating histone mark, to repress host gene expression. ChIP-seq analysis identified 4,870 H3K14 methylated promoter regions, including innate immune genes. Significantly reduced replication of a RomA-deleted strain in host cells was trans-complemented by wild-type, but not by catalytically inactive, RomA. Thus, a secreted L. pneumophila effector targets the host cell nucleus and modifies histones to repress gene expression and promote efficient intracellular replication.
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► Upon infection, L. pneumophila secretes RomA, a SET domain-containing methyltransferase ► RomA triggers H3K14 trimethylation, causing a switch from gene activation to repression ► ChIP-seq identified 4,870 H3K14 methylated promoter regions, including innate immune genes ► RomA SET domain is required for efficient intracellular replication of L. pneumophila
The general view that only adaptive immunity can build immunological memory has recently been challenged. In organisms lacking adaptive immunity, as well as in mammals, the innate immune system can ...mount resistance to reinfection, a phenomenon termed "trained immunity" or "innate immune memory." Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve permanent genetic changes such as mutations and recombination, which are essential for adaptive immunity. The discovery of trained immunity may open the door for novel vaccine approaches, new therapeutic strategies for the treatment of immune deficiency states, and modulation of exaggerated inflammation in autoinflammatory diseases.
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