Membrane-bound pattern recognition receptors (PRRs) are essential for the innate immune system, detecting pathogenic threats and initiating immune responses. This document covers various types of PRRs, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs), each with unique functions in recognizing pathogens and triggering inflammation. Understanding these mechanisms is key for developing antiviral therapies and managing infections.

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.
1. 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.
2. 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.
3. 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.

6. 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.
1. 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.
2. 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).
3. 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.

7. 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.

8. 1. 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.
2. MDA5 (Melanoma differentiation-associated protein 5):
This receptor is adept at recognizing long dsRNA molecules,
which are often produced during viral replication.
3. 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.

9. 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.
1. Common CLRs include Dectin-1, Dectin-2, Mincle, DC-SIGN, and Langerin, each
with distinct ligand specificity and functional roles.
2. 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.

10. 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.
4. 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.
3. 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.

11. • 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

12. 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

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