Membrane-Bound-Pattern-Recognition-Receptors.pptx

Membrane bound PRPs

1. Membrane-Bound Pattern Recognition Receptors Anumol Lorance M.Sc. Microbiology Dept. of Bioscience IGCAS

2. Membrane-Bound Pattern Recognition Receptors Membrane-bound pattern recognition receptors (PRRs) are a critical component of the innate immune system, playing a pivotal role in the early detection and response to pathogenic threats. These specialized receptors are found embedded within the cell membranes of various immune cells, acting as sentinels that continuously scan the extracellular environment for the presence of conserved molecular patterns associated with invading microorganisms or cellular damage. Upon recognizing these pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), the PRRs trigger a cascade of signaling events that activate a coordinated immune response. This rapid activation of the innate immune system is essential for the elimination of infectious agents and the initiation of the adaptive immune response, which provides long-lasting, specific protection against future encounters with the same pathogens .

3. Toll-like receptors (TLRs) Toll-like receptors (TLRs) are a family of membrane-bound pattern recognition receptors (PRRs) that play a crucial role in the innate immune system. These receptors are expressed on the surface of various immune cells, including macrophages, dendritic cells, and epithelial cells, and are responsible for detecting a wide range of pathogen-associated molecular patterns (PAMPs) derived from bacteria, viruses, fungi, and parasites . Structure and Diversity: There are 10 known TLRs in humans (TLR1-TLR10) and 13 in mice, each with a distinct ligand-binding specificity. TLRs are composed of an extracellular domain that recognizes PAMPs, a transmembrane domain, and an intracellular Toll/IL-1 receptor (TIR) domain that initiates downstream signaling cascades. Ligand Recognition: TLRs recognize a diverse array of microbial components, including lipopolysaccharide (LPS) from Gram-negative bacteria, lipoproteins, flagellin, double-stranded RNA, and unmethylated CpG DNA. This broad specificity allows TLRs to detect a wide range of pathogens and initiate appropriate immune responses. Signaling Pathways: Upon ligand binding, TLRs trigger intracellular signaling cascades that involve adaptor proteins, such as MyD88 and TRIF, leading to the activation of transcription factors like NF-κB, AP-1, and IRFs. This activation results in the production of proinflammatory cytokines, chemokines, and type I interferons, which are crucial for the host's defense against pathogens.

4. NOD-like receptors (NLRs) NOD-like receptors (NLRs) are a family of cytoplasmic pattern recognition receptors that play a crucial role in the innate immune system's defense against pathogens and cellular stress. These receptors recognize a diverse range of microbial-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs), triggering signaling cascades that activate inflammatory responses and promote the clearance of harmful agents. The NLR family includes several well-characterized members, such as NOD1, NOD2, NLRP1, NLRP3, and NLRC4, each with their own unique ligand specificity and signaling pathways. For example, NOD1 and NOD2 recognize peptidoglycan fragments from Gram-negative and Gram-positive bacteria, respectively, while NLRP3 senses a wide range of stimuli, including microbial toxins, crystalline structures, and host-derived danger signals . Upon ligand binding, NLRs undergo conformational changes that lead to the recruitment of adapter proteins, such as RIP2 for NOD1/2 or ASC for NLRP3. These adapters then trigger the activation of downstream signaling cascades, including the NF-κB, MAPK, and caspase-1 pathways, resulting in the production of pro-inflammatory cytokines, chemokines, and the initiation of programmed cell death (pyroptosis). The activation of NLRs is tightly regulated to maintain a delicate balance between effective pathogen clearance and the prevention of excessive inflammation, which can lead to tissue damage and autoimmune disorders.

5. RIG-I-like receptors (RLRs) RIG-I-like receptors (RLRs) are a family of cytoplasmic pattern recognition receptors that play a crucial role in the detection of viral infections and the initiation of the innate immune response. These receptors, which include RIG-I, MDA5, and LGP2, are responsible for recognizing the presence of viral RNA within the cytoplasm of host cells. RLRs are particularly adept at sensing the presence of double-stranded RNA (dsRNA), a common byproduct of viral replication. Upon binding to dsRNA, RLRs undergo a conformational change that allows them to interact with the mitochondrial antiviral-signaling (MAVS) protein, which in turn triggers a signaling cascade that leads to the activation of transcription factors such as NF-κB and IRF3/7. These transcription factors then induce the expression of type I interferons and other pro-inflammatory cytokines, which help to mount a robust antiviral response.

6. RIG-I (Retinoic acid-inducible gene I): This receptor is the most well-studied member of the RLR family and is responsible for the detection of 5'-triphosphate RNA, a common feature of viral RNA genomes. MDA5 (Melanoma differentiation-associated protein 5): This receptor is adept at recognizing long dsRNA molecules, which are often produced during viral replication. LGP2 (Laboratory of Genetics and Physiology 2): Although LGP2 does not directly bind to viral RNA, it is believed to play a regulatory role in the RLR signaling pathway, either enhancing or suppressing the activity of RIG-I and MDA5. The activation of RLRs and the subsequent induction of the innate immune response are crucial for the host's ability to mount an effective defense against a wide range of viral pathogens. Understanding the mechanisms by which these receptors function and how they are regulated has important implications for the development of novel antiviral therapies and the management of viral infections.

7. C-type Lectin Receptors (CLRs) C-type lectin receptors (CLRs) are a family of membrane-bound pattern recognition receptors that play a crucial role in the innate immune response. These receptors are characterized by the presence of a carbohydrate-recognition domain (CRD), which allows them to bind to a variety of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). CLRs are primarily expressed on the surface of myeloid cells, such as dendritic cells, macrophages, and neutrophils, as well as on certain epithelial and endothelial cells. Upon recognition of their respective ligands, CLRs trigger signaling cascades that lead to the activation of immune responses, including phagocytosis, cytokine production, and antigen presentation. Common CLRs include Dectin-1, Dectin-2, Mincle, DC-SIGN, and Langerin, each with distinct ligand specificity and functional roles . Dectin-1 is a key CLR that recognizes β-glucans, a major component of fungal cell walls, and can trigger the activation of the NLRP3 inflammasome and the production of proinflammatory cytokines.

8. Overall, C-type lectin receptors are essential components of the innate immune system, serving as crucial sensors for the detection of a diverse array of pathogens and the initiation of appropriate immune responses to maintain host homeostasis and protect against infectious diseases. The signaling pathways activated by CLRs are complex and can involve the recruitment of adaptor proteins, such as Syk and Card9, leading to the activation of transcription factors like NF- κB and NFAT. This, in turn, triggers the expression of genes involved in antimicrobial defense, cytokine production, and the regulation of the immune response. DC-SIGN is a CLR expressed on dendritic cells that can recognize a wide range of pathogens, including viruses, bacteria, and fungi, and plays a crucial role in antigen presentation and the modulation of adaptive immune responses. Mincle recognizes trehalose dimycolate , a glycolipid present in the cell wall of Mycobacterium tuberculosis, and can initiate the production of cytokines and chemokines to combat mycobacterial infections.

9. Scavenger receptors contribute to the recognition and internalization of modified host molecules and microbial components, promoting the clearance of pathogens and cellular debris. Certain scavenger receptors are involved in the uptake of oxidized low-density lipoproteins, linking their function to atherosclerotic plaque formation and cardiovascular diseases. Modulating scavenger receptor activity holds potential for managing atherosclerosis and other inflammatory conditions. Scavenger Receptors

10. Role in Innate Immune Response 1 Pathogen Recognition Membrane-bound pattern recognition receptors (PRRs) play a crucial role in the innate immune response by detecting the presence of pathogenic microorganisms. These receptors recognize unique molecular patterns found on the surface of bacteria, viruses, fungi, and parasites, known as pathogen-associated molecular patterns (PAMPs). This enables the immune system to rapidly detect the presence of infectious agents and initiate a targeted response. 2 Activation of Signaling Cascades Upon recognition of PAMPs, the membrane-bound PRRs, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), undergo conformational changes that trigger the activation of intracellular signaling cascades. These signaling pathways lead to the production of pro-inflammatory cytokines, chemokines, and antimicrobial effector molecules, which help to eliminate the invading pathogens and recruit additional immune cells to the site of infection. 3 Immune Cell Activation The activation of membrane-bound PRRs on the surface of immune cells, such as macrophages, dendritic cells, and natural killer cells, plays a crucial role in the innate immune response. These receptors stimulate the production of inflammatory mediators, the upregulation of co-stimulatory molecules, and the increased phagocytic activity of these cells. This leads to the enhanced recognition and clearance of pathogens, as well as the priming of the adaptive immune response for more targeted and long-lasting protection.

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