Innate Immune Recognition of Nucleic Acids

2010 ◽  
pp. 261-278
Author(s):  
Stefan Bauer
Keyword(s):  
Nucleic Acids ◽  
Innate Immune ◽  
Immune Recognition

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

scholarly journals IMMU-45. CUSTOMIZED LIPID NANOPARTICLES DELIVER NUCLEIC ACIDS TO IMMUNE CELLS IN BRAIN TUMORS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii114-ii114
Author(s):  
Adam Grippin ◽  
Brandon Wummer ◽  
Hector Mendez-Gomez ◽  
Tyler Wildes ◽  
Kyle Dyson ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Nucleic Acids ◽  
Immune Cells ◽  
White Blood Cells ◽  
Lipid Nanoparticles ◽  
Intracranial Tumor ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Normal Brain ◽  
Innate Immune Cells

Abstract BACKGROUND Brain tumors are notoriously difficult to treat in part due to their isolation behind the blood brain barrier and their power to suppress antitumor immune responses. We have previously reported cationic liposome formulations capable of delivering immune modulatory nucleic acids to immune cells in various peripheral organs, but there is currently no reliable method to deliver nucleic acids into brain tumors without direct injection into the tumor site. OBJECTIVE Here, we report the development of a customized lipid nanoparticle to deliver immune modulatory nucleic acids to immune cells in brain tumors. APPROACH Cationic liposomes composed of varying lipid combinations were evaluated for their ability to deliver functional mRNA and siRNA to innate immune cells in vitro and in intracranial tumor models. Nucleic acids were labelled with Cy3 to monitor particle distribution in vivo. RESULTS Lipids composed of DOTAP and cholesterol selectively delivered mRNA and siRNA to intracranial GL261 and KR158b tumors. Interestingly, these particles selectively delivered these nucleic acids to CD45+ white blood cells with minimal delivery to CD45- tumor cells or normal brain tissue. Encapsulation of siRNA blocking programmed death ligand 1 (PDL1) significantly reduced PDL1 expression on innate immune cells in brain tumors, with the greatest effects on tumor-associated macrophages. Co-administration of systemic checkpoint blockade with intravenous administration of these lipid nanoparticles bearing PDL1 siRNA enabled systemic and intratumoral checkpoint blockade, leading to 37% long term survivorship in an otherwise fatal intracranial tumor model. CONCLUSIONS Our customized lipid nanoparticles enable potent intratumoral immune modulation via delivery of nucleic acids to immune cells in brain tumors.

scholarly journals CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells

2005 ◽  
Vol 280 (43) ◽  
pp. 36342-36354 ◽  
Author(s):  
Kristina Elward ◽  
Mark Griffiths ◽  
Masashi Mizuno ◽  
Claire L. Harris ◽  
Jim W. Neal ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Apoptotic Cell ◽  
Membrane Attack Complex ◽  
Factor H ◽  
Innate Immune ◽  
Immune Recognition ◽  
Alternative Pathways ◽  
Complement Regulator ◽  
Complement C1q

Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonself-pathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNase-treated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.

Mediators of innate immune recognition of bacteria concentrate in lipid rafts and facilitate lipopolysaccharide-induced cell activation

2002 ◽  
Vol 115 (12) ◽  
pp. 2603-2611 ◽  
Author(s):  
Martha Triantafilou ◽  
Kensuke Miyake ◽  
Douglas T. Golenbock ◽  
Kathy Triantafilou
Keyword(s):  
Lipid Rafts ◽  
Lipid Raft ◽  
Cell Activation ◽  
Imaging Techniques ◽  
Recognition System ◽  
Innate Immune ◽  
Membrane Microdomains ◽  
Immune Recognition ◽  
Cellular Activation ◽  
Signalling Molecules

The plasma membrane of cells is composed of lateral heterogeneities,patches and microdomains. These membrane microdomains or lipid rafts are enriched in glycosphingolipids and cholesterol and have been implicated in cellular processes such as membrane sorting and signal transduction. In this study we investigated the importance of lipid raft formation in the innate immune recognition of bacteria using biochemical and fluorescence imaging techniques. We found that receptor molecules that are implicated in lipopolysaccharide (LPS)-cellular activation, such as CD14, heat shock protein(hsp) 70, 90, Chemokine receptor 4 (CXCR4), growth differentiation factor 5(GDF5) and Toll-like receptor 4 (TLR4), are present in microdomains following LPS stimulation. Lipid raft integrity is essential for LPS-cellular activation, since raft-disrupting drugs, such as nystatin or MCD, inhibit LPS-induced TNF-α secretion. Our results suggest that the entire bacterial recognition system is based around the ligation of CD14 by bacterial components and the recruitment of multiple signalling molecules, such as hsp70, hsp90, CXCR4, GDF5 and TLR4, at the site of CD14-LPS ligation, within the lipid rafts.

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