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3-2 Advances in RNA Sensing by the Immune System Separation of siRNA Unwanted Effects from RNA Inter
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Creative BioLabs is a contract research organization based in New York that specializes in antibody discovery, antibody engineering, and biomanufacturing solutions. They are discussing immune stimulation and small interfering RNA (siRNA) for activating innate and acquired immunity against cancer and virus-infected cells. They explain the differences between innate and acquired immunity, and the role of Toll-like receptors in recognizing pathogen-related molecular patterns. They also mention other receptors involved in recognizing nucleic acids, such as RNA helicases and Toll-like receptors 3, 7, 8, and 9. Toll-like receptors can recognize different substrates and induce immune cells, particularly plasma-like dendritic cells, to produce immune responses. However, the recognition of self-nucleic acids by Toll-like receptors can lead to autoimmune diseases. Welcome to Creative BioLabs, 100% of the effort, 100% of the service. As a dynamic contract research organization, we are based in New York and serve the whole world. Our seasoned scientists are skilled in antibody discovery, antibody engineering, and biomanufacturing solutions. Good evening, dear friends. Nice to have you here with us again. At the end of the last program, our researchers David mentioned a conjecture that immune-stimulating small interfering RNA may help to activate innate and acquired immunity against cancer and virus-infected cells. Immune activation is beneficial to some diseases. Today, David will continue to enlighten us on immune stimulation and small interfering RNA. Thanks for being here, David. Thank you for inviting me. Very excited to be here. Let's continue with our discussion on the small interfering RNA. But before we get to immune activation, I'd like to briefly review the key points of innate immunity and acquired immunity. The innate immune system includes a series of cells and related mechanisms, which can resist foreign infection in a non-specific way. The innate immune system does not provide lasting protective immunity, but exists in all animals and plants as a rapid anti-infective effect. Specific immunity, also known as acquired immunity or adaptive immunity, only targets one pathogen. It's acquired infection or artificial vaccination of the body to resist infection. It is usually formed after the stimulation of microorganisms and other antigen substances and can react specifically with the antigen. It is worth noting that the innate immune system has developed germline pattern recognition receptors, which promote rapid response to microbial pathogens in the invasion stage. These receptors recognize conserved pathogen-associated molecular pattern, which does not exist in the host and are usually important for the pathogenicity and survival of pathogens. What are the pathogen-related molecular patterns? Are they special structures of a pathogen? In short, pathogen-related molecular patterns are unique to microorganisms, such as lipopolysaccharide, peptidoglycan, capsule structure, bacterial flagellin, bacterial DNA, bacterial lipid, viral RNA and viral glycoprotein. Can you tell us what the main receptors are that can recognize pathogen-related molecular patterns in the host? Sure. I would say the Toll-like receptors. They play an important role in the activation of pathogen-derived products and innate and acquired immunities. They are type 1 transmembrane proteins, which are evolutionarily conserved between insects and vertebrates. When people were studying the key genes involved in the process of ventral-dorsal differentiation in the Drosophila embryo development model in Drosophila melanogaster, Toll was first identified as the basic protein controlling the dorsal-ventral pattern of the embryo and then became the key protein of antifungal immune response in adult Drosophila melanogaster. What about Toll-like receptors in vertebrates? Up to now, 13 members of the receptors have been reported in vertebrates, which are essential for pathogen detection. In humans, 10 functional Toll-like receptors have been identified and proved to be able to detect pathogen-derived compounds. They are expressed on the cell surface or in intracellular vesicles or organelles. We divide the structure of the Toll-like receptors into two parts, intracellular domain and extracellular domain. The extracellular domain is characterized by a large number of leucine-rich repeats that can recognize a wide range of viral, bacterial, and fungal structures and interact with other Toll-like receptors. The heterodimer or homodimer formed is very important for the activity of the receptor. Then the intracellular domains, all of them contain the tear domain, which links recognition signals with intracellular pathways. What happens when Toll-like receptor is activated? If we are talking about the ligand-driven TLR activation, two major signaling pathways are activated. One of these pathways requires the adapter molecule MyD88, which leads to the production of type 1 interferon or NF-kappa-B dependent pro-inflammatory cytokines, including tumor necrosis factor alpha and interleukin-12. In contrast, the second pathway requires the adapter molecule, TRIF, which mainly induces interferon production. You mentioned before that Toll-like receptors are transmembrane proteins. But how are they expressed in immune cells? Right. In immune cells, Toll-like receptors that recognize nucleic acids are only expressed in endosomes. These include Toll-like receptors 3, Toll-like receptors 7 or 8, and Toll-like receptors 9, which sense double-stranded RNAs, single-stranded RNA, and single-stranded DNA, respectively. Other Toll-like receptors, in contrast, reside on the cell membrane. These include Toll-like receptors 2, 4, 5, and 11, which recognize lipopeptides, lipopolysaccharides, flagellin, and propellin. Are there any other receptors that can recognize the nucleic acids of pathogens, besides Toll-like receptors? We already know that, as part of the innate defense mechanism against invasive pathogens, the mammalian immune system is activated by microbial RNA and DNA, which then lead to the production of type 1 interferon and pro-inflammatory cytokines. The first double-stranded RNA sensor identified is double-stranded RNA-dependent protein kinase, which can phosphorylate serine and threonine residues of the target protein. Does this kind of protein kinase exist in cells? Most human cells do. They structurally express low levels of double-stranded RNA-dependent protein kinases, but remain inactive. However, once a pathogen invades a cell, the kinase binds to double-stranded RNA, then forms homodomers, leading to their phosphorylation and activation. Which proteins will be affected by activated protein kinases? Or which proteins serve as their substrates? A large number of them, especially the translation-initiation factor ELF2-alpha. It is an important step of antivirus drug resistance to induce translation arrest and apoptosis. And also the IKK-beta is phosphorylated by the activated kinases, to further activate the NF-kappa-B signaling pathway. You just said antivirus drug resistance, which reminded me of another protein, stimulated by long double-stranded RNA and oligodenylate synthase structurally, expressed in the process of antiviral response. Double-stranded RNA-dependent protein kinases and oligodenylate synthetases are both used as double-stranded RNA sensors. What is the difference between them? Although they both are related to antiviral immunity, protein kinases receptors and ribonucleus L are mainly interferon effects, which are not necessary in the initial stage of interferon production. In fact, targeting of the protein kinases receptors gene in mice suggest that it is not necessary to respond to interferon in response to viral infection. Therefore, other cytoplasmic receptors may be involved. What other cell receptors might be involved in the recognition of antiviral immunity? In the recognition of pathogen RNA? Do we know that? Yes, but just recently. RNA helicases retinoic acid inducible gene 1 and melanoma differentiation related gene 5 have been identified as the major cytoplasmic receptors of viral RNA. Related studies have shown that a mice with RNA helicases retinoic acid inducible gene 1 deletion were found to be highly sensitive to virus infection. RNA helicases are widely expressed in the inactive form. Like other antiviral proteins, their expression levels were also determined by interferon alpha and interferon beta rays. Furthermore, RNA helicases retinoic acid inducible gene 1 encodes not only the RNA helicase domain, but also the caspase recruitment domain at N-terminal. Can you elaborate more on how RNA helicase performs its function? RNA helicase domain is responsible for the recognition of viral double-stranded RNA and the induction of conformational changes resulting in the interaction between RNA helicases retinoic acid inducible gene 1 caspase recruitment domain and another adapter protein containing caspase recruitment domain. And to do these, it needs ATPase activity. Some data show that, although RNA helicases retinoic acid inducible gene 1 seems to be an important receptor of viral RNA, microbial nucleic acids can also be recognized by toll-like receptors, especially in immune cells. Can you explain this part to us? Yes. In the toll-like receptor family, TLR3, 7, 8 and 9 are expressed in cells and can recognize nucleic acids. However, TLR3, 7, 8 and 9 are mostly expressed on the plasma membrane and are used to detect bacterial components. This cellular-targeted immune function is more likely to sense viral RNA during infection. TLR3 is also expressed on the cell surface and is thought to recognize extracellular virus double-stranded RNA. Which substrates can these toll-like receptors recognize? Well, you know different receptors have different preferences. For example, TLR7 and TLR8 recognize viral single-stranded RNA and small molecule synthetic compounds that can induce immune cells to produce type 1 interferon and interleukin 12. And TLR9 recognizes unmethylated DNA motifs that exist in both viral and bacterial DNA but are inhibited or methylated in vertebrate genomes. However, the structural difference between eukaryotic and prokaryotic DNA may not be the only mechanism to distinguish self-nucleic acids from non-self-nucleic acids. This is because toll-like receptors can recognize their own nucleic acid under some conditions, which leads to the occurrence of autoimmune diseases. You said they induce immune cells. And what kinds of immune cells are we talking about here? Mainly plasma-like dendritic cells. And they react to viral nucleic acid, which is absorbed into cell through endocytosis. Plasma-like dendritic cells belong to a unique subset of dendritic cells, which have the special function of secreting type 1 interferon. Thank you for sharing your knowledge with us. In today's episode, we talked about that as part of the innate defense mechanism against invasive pathogens. The mammalian immune system is activated by microbial RNA and DNA, leading to the production of type 1 interferon and pro-inflammatory cytokines. Toll-like receptors play an important role in the activation of pathogen-derived products and innate and acquired immunity. In addition, other cytoplasmic receptors are also involved in the response of interferon to viral infection. These include protein kinase receptors, oligodenylate synthase, RNA helicases, and so on. That's the end of today's program. Thank you for listening. We will continue our discussions in the next episode.
