Source: http://www.asmscience.org/content/book/10.1128/9781555816650.ch09
Timestamp: 2019-04-26 05:54:53+00:00

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This chapter discusses the current knowledge concerning the cytosolic pattern recognition receptors (PRRs), the responses they trigger, their physiological role during infection, and their regulation. It describes the diseases associated with mutations in several of these PRRs or associated proteins. Viruses can be detected through recognition of their nucleic acids either extracellularly or in the endosomes by Toll-like receptors (TLRs). The host cell signaling pathways that lead to caspase-1 activation in macrophages infected with three bacterial pathogens that replicate in the host cell cytosol-the gram-positive bacterium L. monocytogenes and the gram-negative bacteria S. flexneri and F. tularensis-have been studied so far. The various responses triggered after engagement of cytosolic PRRs are critical to fight infections, but some pathogens have virulence factors that block the innate immune signaling. The chapter reviews some recent examples of positive and negative regulation of cytosolic PRR signaling. It is likely that as we gain more insight into the different intracellular signaling pathways, we will find that many pathogens have evolved mechanisms to modulate and evade these pathways. While these pathways are highly regulated, some PRR mutations lead to a number of autoinflammatory diseases. A better understanding of the role of these PRRs during the normal innate immune response to intracellular pathogens is likely to give us a better understanding of the autoinflammatory diseases and will lead to the development of new therapeutics.
Nonself nucleic acids within the host cytosol trigger type I IFN secretion. Viruses, and possibly intracellular bacteria, release nonself nucleic acids into the host cytosol that are recognized by the PRRs RIG-I, MDA-5, and DAI. PRRs signal through the adaptor MAVS, the E3-ubiquitin ligase TRAF3, and the kinases TBK-1 and IKKi, leading to phosphorylation of the transcription factor IRF3. Phosphorylated IRF3 dimerizes and translocates into the nucleus, where it binds ISREs and induces transcription of numerous genes including ifn-β.
Bacterial cell wall fragments within the host cytosol trigger MAPK and NF-κB activation. Peptidoglycan fragments from various intracellular and extracellular bacteria can be delivered into the host cytosol, where they are recognized by the PRRs NOD1 or NOD2. The PRRs signal through the adaptor RIP2. RIP2 engagement leads to IκB phosphorylation in a NEMO- and TAK1-dependent manner resulting in its degradation and the translocation of NF-κB into the nucleus. Nuclear NF-κB induces the transcription of numerous proinflammatory genes including IL-8. NOD1/2 engagement also leads to MAP kinase activation through RIP2 and the tripartite complex CARD9-Bcl10-Malt1.
Flagellin and other unknown bacterial molecules trigger caspase-1 activation within various inflammasomes. The LRRs of the PRRs are the proposed ligand binding domains. Upon binding, a modification of conformation releases the accessibility of the NBD, allowing the PRR to interact through homotypic interactions with other partners including the adaptor ASC. ASC can oligomerize and interact both with the PRRs containing a pyrin domain and procaspase-1, leading to the formation of a multimolecular complex called the inflammasome. Dimerization of procaspase-1 within the inflammasome leads to its autocatalytic activation. Mature caspase-1 consists of a heterotetramer possessing a cysteine protease activity responsible for maturation of proinflammatory cytokines and triggering cell death of the host cell. The nature of the IPAF inflammasomes and the protein responsible for direct binding of flagellin are still unknown; three possible models are presented.
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