scholarly journals The immunorecognition, subcellular compartmentalization, and physicochemical properties of nucleic acid nanoparticles can be controlled by composition modification

2020 ◽  
Vol 48 (20) ◽  
pp. 11785-11798
Author(s):  
Morgan Brittany Johnson ◽  
Justin R Halman ◽  
Daniel K Miller ◽  
Joseph S Cooper ◽  
Emil F Khisamutdinov ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Targeted Delivery ◽  
Inflammatory Responses ◽  
Diagnostic Tools ◽  
Immune Recognition ◽  
Composition Modification ◽  
Target Molecules ◽  
Subcellular Compartmentalization

Abstract Nucleic acid nanoparticles (NANPs) have become powerful new platforms as therapeutic and diagnostic tools due to the innate biological ability of nucleic acids to identify target molecules or silence genes involved in disease pathways. However, the clinical application of NANPs has been limited by factors such as chemical instability, inefficient intracellular delivery, and the triggering of detrimental inflammatory responses following innate immune recognition of nucleic acids. Here, we have studied the effects of altering the chemical composition of a circumscribed panel of NANPs that share the same connectivity, shape, size, charge and sequences. We show that replacing RNA strands with either DNA or chemical analogs increases the enzymatic and thermodynamic stability of NANPs. Furthermore, we have found that such composition changes affect delivery efficiency and determine subcellular localization, effects that could permit the targeted delivery of NANP-based therapeutics and diagnostics. Importantly, we have determined that altering NANP composition can dictate the degree and mechanisms by which cell immune responses are initiated. While RNA NANPs trigger both TLR7 and RIG-I mediated cytokine and interferon production, DNA NANPs stimulate minimal immune activation. Importantly, incorporation of 2′F modifications abrogates RNA NANP activation of TLR7 but permits RIG-I dependent immune responses. Furthermore, 2′F modifications of DNA NANPs significantly enhances RIG-I mediated production of both proinflammatory cytokines and interferons. Collectively this indicates that off-target effects may be reduced and/or desirable immune responses evoked based upon NANPs modifications. Together, our studies show that NANP composition provides a simple way of controlling the immunostimulatory potential, and physicochemical and delivery characteristics, of such platforms.

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 Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

2021 ◽  
Vol 12 ◽  
Author(s):  
Clara Taffoni ◽  
Alizée Steer ◽  
Johanna Marines ◽  
Hanane Chamma ◽  
Isabelle K. Vila ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Dna Damage Response ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Fine Tuning ◽  
Innate Immune Activation ◽  
Damage Response

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

scholarly journals Multifunctional Immunoadjuvants for Use in Minimalist Nucleic Acid Vaccines

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 644
Author(s):  
Saed Abbasi ◽  
Satoshi Uchida
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Innate Immune ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Subunit Vaccines ◽  
Adaptive Immune ◽  
Nucleic Acid Vaccines ◽  
And Control

Subunit vaccines based on antigen-encoding nucleic acids have shown great promise for antigen-specific immunization against cancer and infectious diseases. Vaccines require immunostimulatory adjuvants to activate the innate immune system and trigger specific adaptive immune responses. However, the incorporation of immunoadjuvants into nonviral nucleic acid delivery systems often results in fairly complex structures that are difficult to mass-produce and characterize. In recent years, minimalist approaches have emerged to reduce the number of components used in vaccines. In these approaches, delivery materials, such as lipids and polymers, and/or pDNA/mRNA are designed to simultaneously possess several functionalities of immunostimulatory adjuvants. Such multifunctional immunoadjuvants encode antigens, encapsulate nucleic acids, and control their pharmacokinetic or cellular fate. Herein, we review a diverse class of multifunctional immunoadjuvants in nucleic acid subunit vaccines and provide a detailed description of their mechanisms of adjuvanticity and induction of specific immune responses.

scholarly journals Facile Construction of a Solely-DNA-Based System for Targeted Delivery of Nucleic Acids

Nanomaterials ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1967
Author(s):  
Ziwen Dai ◽  
Juan Li ◽  
Yongfang Lin ◽  
Zhigang Wang ◽  
Yang Huang
Keyword(s):  
Drug Delivery ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Drug Delivery System ◽  
Delivery System ◽  
Targeted Delivery ◽  
Dna Aptamers ◽  
Dna Nanostructures ◽  
Dna Strands ◽  
Targeting Ability

We designed a functional drug delivery system based solely on DNA. The whole system was built with only four DNA strands. Cyclization of DNA strands excluded the formation of byproducts. DNA aptamers were equipped to endow triangular DNA nanostructures with targeting ability. The homogeneity of materials enabled not only facile construction but also convenient loading of nucleic acid-based drugs with much ease.

scholarly journals RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

2013 ◽  
Vol 210 (11) ◽  
pp. 2447-2463 ◽  
Author(s):  
Cherilyn M. Sirois ◽  
Tengchuan Jin ◽  
Allison L. Miller ◽  
Damien Bertheloot ◽  
Hirotaka Nakamura ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Inflammatory Responses ◽  
Immune Recognition ◽  
Dna Uptake ◽  
Rna Molecules ◽  
Receptor Complexes ◽  
Dna And Rna ◽  
Signaling Receptors ◽  
Mammalian Immune System

Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE–DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.

scholarly journals The Recognition of and Reactions to Nucleic Acid Nanoparticles by Human Immune Cells

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4231
Author(s):  
Dominika Bila ◽  
Yasmine Radwan ◽  
Marina A. Dobrovolskaia ◽  
Martin Panigaj ◽  
Kirill A. Afonin
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Cells ◽  
Current Knowledge ◽  
Cytokine Response ◽  
Clinical Settings ◽  
Immune Recognition ◽  
Additional Tool ◽  
Cpg Oligonucleotides ◽  
Essential Components

The relatively straightforward methods of designing and assembling various functional nucleic acids into nanoparticles offer advantages for applications in diverse diagnostic and therapeutic approaches. However, due to the novelty of this approach, nucleic acid nanoparticles (NANPs) are not yet used in the clinic. The immune recognition of NANPs is among the areas of preclinical investigation aimed at enabling the translation of these novel materials into clinical settings. NANPs’ interactions with the complement system, coagulation systems, and immune cells are essential components of their preclinical safety portfolio. It has been established that NANPs’ physicochemical properties—composition, shape, and size—determine their interactions with immune cells (primarily blood plasmacytoid dendritic cells and monocytes), enable recognition by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and mediate the subsequent cytokine response. However, unlike traditional therapeutic nucleic acids (e.g., CpG oligonucleotides), NANPs do not trigger a cytokine response unless they are delivered into the cells using a carrier. Recently, it was discovered that the type of carrier provides an additional tool for regulating both the spectrum and the magnitude of the cytokine response to NANPs. Herein, we review the current knowledge of NANPs’ interactions with various components of the immune system to emphasize the unique properties of these nanomaterials and highlight opportunities for their use in vaccines and immunotherapy.

scholarly journals Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Okude ◽  
Daisuke Ori ◽  
Taro Kawai
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Inflammatory Diseases ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Sensor Molecules

Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is essential for eliciting antiviral immune responses by inducing the production of type I interferons (IFNs) and proinflammatory cytokines. Such responses are a prerequisite for mounting innate and pathogen-specific adaptive immune responses. However, host cells also use nucleic acids as carriers of genetic information, and the aberrant recognition of self-nucleic acids by PRRs is associated with the onset of autoimmune or autoinflammatory diseases. In this review, we describe the mechanisms of nucleic acid sensing by PRRs, including Toll-like receptors, RIG-I-like receptors, and DNA sensor molecules, and their signaling pathways as well as the disorders caused by uncontrolled or unnecessary activation of these PRRs.

Cytoplasmic Mechanisms of Recognition and Defense of Microbial Nucleic Acids

2018 ◽  
Vol 34 (1) ◽  
pp. 357-379 ◽  
Author(s):  
Ming-Ming Hu ◽  
Hong-Bing Shu
Keyword(s):  
Immune Response ◽  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Posttranslational Modifications ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Organelle Trafficking ◽  
Signaling Components ◽  
Cellular Organelles

Microbial nucleic acids are major signatures of invading pathogens, and their recognition by various host pattern recognition receptors (PRRs) represents the first step toward an efficient innate immune response to clear the pathogens. The nucleic acid–sensing PRRs are localized at the plasma membrane, the cytosol, and/or various cellular organelles. Sensing of nucleic acids and signaling by PRRs involve recruitment of distinct signaling components, and PRRs are intensively regulated by cellular organelle trafficking. PRR-mediated innate immune responses are also heavily regulated by posttranslational modifications, including phosphorylation, polyubiquitination, sumoylation, and glutamylation. In this review, we focus on our current understanding of recognition of microbial nucleic acid by PRRs, particularly on their regulation by organelle trafficking and posttranslational modifications. We also discuss how sensing of self nucleic acids and dysregulation of PRR-mediated signaling lead to serious human diseases.

scholarly journals Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era

2022 ◽  
Vol 12 ◽  
Author(s):  
Leila Abdelhamid ◽  
Xin M. Luo
Keyword(s):  
Immune System ◽  
Environmental Factors ◽  
Immune Responses ◽  
Host Defense ◽  
Lupus Erythematosus ◽  
Inflammatory Responses ◽  
Immune Recognition ◽  
Systemic Autoimmunity ◽  
Hygiene Measures ◽  
Autoimmune Conditions

The immune system is an efficiently toned machinery that discriminates between friends and foes for achieving both host defense and homeostasis. Deviation of immune recognition from foreign to self and/or long-lasting inflammatory responses results in the breakdown of tolerance. Meanwhile, educating the immune system and developing immunological memory are crucial for mounting defensive immune responses while protecting against autoimmunity. Still to elucidate is how diverse environmental factors could shape autoimmunity. The emergence of a world pandemic such as SARS-CoV-2 (COVID-19) not only threatens the more vulnerable individuals including those with autoimmune conditions but also promotes an unprecedented shift in people’s dietary approaches while urging for extraordinary hygiene measures that likely contribute to the development or exacerbation of autoimmunity. Thus, there is an urgent need to understand how environmental factors modulate systemic autoimmunity to better mitigate the incidence and or severity of COVID-19 among the more vulnerable populations. Here, we discuss the effects of diet (macronutrients and micronutrients) and hygiene (the use of disinfectants) on autoimmunity with a focus on systemic lupus erythematosus.

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