Hubbry Logo
Pathogen-associated molecular patternPathogen-associated molecular patternMain
Open search
Pathogen-associated molecular pattern
Community hub
Pathogen-associated molecular pattern
logo
7 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Pathogen-associated molecular pattern
Pathogen-associated molecular pattern
Pathogen-associated molecular pattern
View on Wikipedia
from Wikipedia

Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes, but not present in the host.[1] They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals.[2] This allows the innate immune system to recognize pathogens and thus, protect the host from infection.[3]: 494 

This initiation of the immune response consists of the secretion of inflammatory cytokines and chemokines.[4] PAMPs can initiate the maturation of immune cells, which can travel to the primary lymph node and trigger the adaptive immune system that involves the production of antibodies against specific antigens.[5]

Although the term "PAMP" is relatively new, the concept that molecules derived from microbes must be detected by receptors from multicellular organisms has been held for many decades, and references to an "endotoxin receptor" are found in much of the older literature. The recognition of PAMPs by the PRRs triggers activation of several signaling cascades in the host immune cells like the stimulation of interferons (IFNs)[6] or other cytokines.[7]

Role in the Immune System

[edit]

Cells that promote innate immunity (dendritic cells, macrophages, neutrophils, and more) express PRRs. Not only do PPRs detect PAMPs, they also detect host-derived damage-associated molecular patterns or DAMPs that are products of tissue damage. Toll-like receptors (TLR), complement receptors (CR), and scavenger receptors are among the many types of PRRs that monitor the cellular environment for invaders and damage.[8] The innate and adaptive immune systems are connected through TLRs because it leads to the secretion of cytokines and chemokines that go on to help recruit lymphocytes.

Innate Immunity

[edit]

When an antigen breaches the protective barrier (skin, body hair, gastrointestinal tract, etc) and enters the tissue or the bloodstream, the initial response is known as the innate immune system.[9] PAMPs are critical to the initiation of the innate immune system because they recognize the danger, which will result in a response against the threat. PAMPs interacting with PRRs initiate signaling pathways that produce chemokines and pro-inflammatory cytokines–creating an inflammatory environment.[10]

The cytokines and chemokines secreted lead to the translocation of dendritic cells that activate T cells, which "help" B-cells secrete antigen-specific antibodies, which is associated with the adaptive immune response. None of these events can occur without the PRR–PAMPs interaction.[11]

Types

[edit]

A vast array of different types of molecules can serve as PAMPs, including glycans and glycoconjugates.[12] Flagellin is also another PAMP that is recognized via the constant domain, D1 by TLR5.[13] Despite being a protein, its N- and C-terminal ends are highly conserved, due to its necessity for function of flagella.[14] Nucleic acid variants normally associated with viruses, such as double-stranded RNA (dsRNA), are recognized by TLR3 and unmethylated CpG motifs are recognized by TLR9.[15] The CpG motifs must be internalized in order to be recognized by TLR9.[14] Viral glycoproteins, as seen in the viral-envelope, as well as fungal PAMPS on the cell surface or fungi are recognized by TLR2 and TLR4.[14]

Gram-negative bacteria

[edit]

Bacterial lipopolysaccharides (LPSs), also known as endotoxins, are found on the cell membranes of gram-negative bacteria,[16] are considered to be the prototypical class of PAMPs. The lipid portion of LPS, lipid A, contains a diglycolamine backbone with multiple acyl chains. This is the conserved structural motif that is recognized by TLR4, particularly the TLR4-MD2 complex.[17][18] Microbes have two main strategies in which they try to avoid the immune system, either by masking lipid A or directing their LPS towards an immunomodulatory receptor.[17]

Peptidoglycan (PG) is also found within the membrane walls of gram-negative bacteria[19] and is recognized by TLR2, which is usually in a heterodimer of with TLR1 or TLR6.[20][14]

Gram-positive bacteria

[edit]

Lipoteichoic acid (LTA) from gram-positive bacteria, bacterial lipoproteins (sBLP), a phenol soluble factor from Staphylococcus epidermidis, and a component of yeast walls called zymosan, are all recognized by a heterodimer of TLR2[20] and TLR1 or TLR6.[14] However, LTAs result in a weaker pro-inflammatory response compared to lipopeptides, as they are only recognized by TLR2 instead of the heterodimer.[17]

Viruses

[edit]

Viral DNA, viral RNA and CpG are the PAMPs associated with viruses. The PRRs that sense viruses are TLRs, RLRs (Rig-I-like receptors), CLRs (C-type lectine receptors), and inflammasomes/DNA sensors.[21] CLRs are mainly located on myeloid cells, and RLRs are cytoplasmic, mainly detecting viral RNA. TLRs can be located on cell surfaces and the endosomal membrane. Bacterial infections can be intracellular and extracellular, while viral infections are largely intracellular, so endosomal TLRs are most associated with virus detection.[22]

TLR3 recognizes dsDNA while TLR7 and TLR8 detect ssRNA. TLR9's detection of hypomethylated CpG DNA could differentiate virus from self molecules because of the higher CpG content in viruses. PAMPs recognition by TLR is followed by signaling pathways. Viruses may evade the immune response by interacting with proteins in these signaling pathways. By attacking the proteins involved in these pathways, viruses can attempt to evade their destruction.[21]

In mycobacteria

[edit]

Mycobacteria are intracellular bacteria which survive in host macrophages. The mycobacterial wall is composed of lipids and polysaccharides and also contains high amounts of mycolic acid. Purified cell wall components of mycobacteria activate mainly TLR2 and also TLR4. Lipomannan and lipoarabinomannan are strong immunomodulatory lipoglycans.[23] TLR2 with association of TLR1 can recognize cell wall lipoprotein antigens from Mycobacterium tuberculosis, which also induce production of cytokines by macrophages.[24] TLR9 can be activated by mycobacterial DNA.

History

[edit]

First introduced by Charles Janeway in 1989, PAMP was used to describe microbial components that would be considered foreign in a multicellular host.[17] The term "PAMP" has been criticized on the grounds that most microbes, not only pathogens, express the molecules detected; the term microbe-associated molecular pattern (MAMP),[25][26][27] has therefore been proposed. A virulence signal capable of binding to a pathogen receptor, in combination with a MAMP, has been proposed as one way to constitute a (pathogen-specific) PAMP.[28] Plant immunology frequently treats the terms "PAMP" and "MAMP" interchangeably, considering their recognition to be the first step in plant immunity, PTI (PAMP-triggered immunity), a relatively weak immune response that occurs when the host plant does not also recognize pathogenic effectors that damage it or modulate its immune response.[29]

See also

[edit]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pathogen-associated molecular pattern

View on Grokipedia
from Grokipedia
Pathogen-associated molecular patterns (PAMPs) are highly conserved molecular structures or motifs shared by diverse pathogenic microorganisms, including , viruses, fungi, and , that are essential for microbial survival and viability but absent in host cells. These patterns encompass a variety of biomolecules, such as lipopolysaccharides (LPS) from Gram-negative bacterial outer membranes, and lipoteichoic acids from bacterial cell walls, from bacterial flagella, and double-stranded from viral genomes. The concept of PAMPs was first articulated by immunologist Charles A. Janeway Jr. in 1989 as part of his hypothesis, which revolutionized understanding of innate immunity by positing that germline-encoded receptors could detect broad microbial signatures to bridge innate and adaptive responses. In the , PAMPs serve as critical danger signals that alert host cells to the presence of infection, enabling rapid discrimination between self and non-self entities. They are detected by receptors (PRRs), a family of evolutionarily conserved sensors expressed on immune cells like macrophages, dendritic cells, and epithelial cells, as well as on non-immune cells. Key PRR classes include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and C-type lectin receptors (CLRs), which bind PAMPs through specialized ligand-recognition domains such as leucine-rich repeats (LRRs). Upon binding, PAMP-PRR interactions trigger intracellular signaling cascades—often involving adaptor proteins like MyD88 or CARD domain-containing molecules—that activate transcription factors such as , leading to the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β), type I interferons, and . This PAMP-driven activation not only mounts immediate antimicrobial defenses, such as and complement activation, but also primes adaptive immunity by promoting and T-cell on dendritic cells. Dysregulated PAMP recognition can contribute to pathological in conditions like or autoimmune diseases, while therapeutic strategies targeting PAMPs or PRRs, such as TLR agonists, are being explored for vaccines and immunotherapies. Overall, PAMPs represent a foundational mechanism by which multicellular organisms have co-evolved with microbes to ensure survival against infectious threats.

Definition and Properties

Definition

Pathogen-associated molecular patterns (PAMPs) are conserved molecular motifs or structures that are characteristic of microbial pathogens, including , viruses, fungi, and parasites, and are typically absent from healthy host cells. These patterns represent essential components of pathogens that enable the host to distinguish between self and non-self entities. The concept of PAMPs was introduced by Charles A. Janeway Jr. in 1989, who proposed that the relies on the recognition of such shared microbial patterns to mount rapid defensive responses. Janeway's framework emphasized that these patterns are not random but serve as reliable indicators of infection due to their evolutionary conservation. Key attributes of PAMPs include their high degree of conservation across classes, which stems from their critical role in survival and replication, making them indispensable and thus infrequently altered by evolutionary pressures. As danger signals, PAMPs trigger host immune activation upon detection, alerting cells to the presence of potential threats without requiring prior exposure to the specific . This recognition occurs through pattern recognition receptors (PRRs) expressed on immune and non-immune cells.

Key Characteristics

Pathogen-associated molecular patterns (PAMPs) exhibit remarkable structural diversity, encompassing a range of molecular classes essential for microbial viability. These include carbohydrates such as , lipids like , proteins exemplified by , and nucleic acids such as unmethylated CpG DNA. This diversity allows PAMPs to serve as reliable indicators of microbial presence across various pathogen types. Functionally, PAMPs are typically surface-exposed or secreted components of microbes that remain invariant under evolutionary pressures, as alterations would compromise survival. Their conservation enables them to elicit rapid, non-specific immune responses in hosts, activating innate defenses without prior exposure to the . From an evolutionary standpoint, PAMPs embody ancient, conserved microbial features critical for fitness, such as essential metabolic or structural roles, which have persisted due to their indispensability. This retention facilitates broad-spectrum recognition by host immune systems across diverse , providing an effective first line of defense against . In contrast, damage-associated molecular patterns (DAMPs) are endogenous host-derived molecules released during cellular stress or .

Recognition Mechanisms

Pattern Recognition Receptors

Pattern recognition receptors (PRRs) constitute a diverse array of germline-encoded sensors that directly bind pathogen-associated molecular patterns (PAMPs), initiating innate immune detection across various host compartments. These receptors are expressed on immune cells such as macrophages, dendritic cells, and epithelial cells, as well as non-immune tissues, enabling rapid discrimination between microbial invaders and host components. PRRs are broadly categorized by their structural motifs and subcellular localization, encompassing membrane-bound, cytosolic, and soluble forms, each adapted to monitor distinct microenvironments for PAMP exposure. The (TLR) family represents one of the most well-characterized PRR classes, originally discovered as mammalian homologs of the Toll protein essential for antifungal defense. In humans, there are 10 functional TLRs, which are type I transmembrane proteins featuring extracellular leucine-rich repeats for binding and intracellular Toll/interleukin-1 receptor domains. Surface TLRs (e.g., TLR1, TLR2, TLR4, TLR5, TLR6) reside on the plasma membrane of sentinel cells, recognizing extracellular PAMPs such as bacterial lipopeptides and (LPS), with TLR4 serving as a prototypical example for LPS detection via accessory molecules like MD-2 and CD14. Endosomal TLRs (e.g., TLR3, TLR7, TLR8, TLR9), localized within intracellular vesicles, specialize in nucleic acid PAMPs, including double-stranded (TLR3) and unmethylated CpG DNA (TLR9), facilitating surveillance during or . This compartmentalization ensures TLRs probe both external and internalized threats with high specificity. NOD-like receptors (NLRs) form another pivotal intracellular family, comprising over 20 members in humans characterized by a central nucleotide-binding oligomerization domain flanked by sensor and effector regions. Exclusively cytosolic, NLRs monitor the intracellular milieu for PAMPs that evade extracellular detection, such as bacterial fragments. For instance, NOD1 detects γ-D-glutamyl-diaminopimelic acid-containing peptidoglycans prevalent in , while NOD2 recognizes muramyl dipeptide from both Gram-positive and Gram-negative sources, enabling broad yet selective bacterial sensing. NLRs' cytosolic positioning allows them to integrate signals from breached cellular barriers, distinguishing invasive pathogens from commensals. C-type lectin receptors (CLRs) are a superfamily of carbohydrate-binding proteins, many of which function as PRRs through calcium-dependent recognition domains. Predominantly membrane-bound on myeloid cells, CLRs like the and DC-SIGN bind and residues on microbial surfaces, while others such as Dectin-1, discovered as a sensor, localize to the cell surface or endosomes to engage fungal and mycobacterial . Dectin-1 exemplifies CLR specificity with its recognition of β-1,3-glucans, a conserved across fungal cell walls, allowing targeted detection of eukaryotic pathogens. This family’s emphasis on glycan epitopes complements other PRRs by addressing carbohydrate-rich microbial features. RIG-I-like receptors (RLRs), including RIG-I, , and LGP2, are soluble cytosolic sensors specialized for viral nucleic acids, identified as RNA helicases with DEAD-box motifs for ATP-dependent unwinding. RIG-I preferentially binds short, 5'-triphosphate-bearing double-stranded RNAs typical of many RNA viruses, whereas recognizes longer double-stranded RNAs, such as those produced during replication, providing complementary coverage of strategies. Their cytoplasmic localization positions RLRs as key detectors of cytosolic viral invasion, with ligand specificity dictated by RNA structure and modification status. Beyond these anchored families, secreted PRRs such as collectins patrol extracellular fluids, including serum and mucosal surfaces. Collectins, exemplified by mannose-binding lectin (MBL), feature collagen-like tails and domains that oligomerize into multimeric structures for enhanced . MBL binds , , and on surfaces, facilitating opsonization and complement activation, thus extending PRR surveillance to soluble phases. Overall, the combinatorial specificity of PRR families—membrane-bound for surface/endosomal threats, cytosolic for internal breaches, and secreted for humoral monitoring—enables nuanced classification and immune priming.

Immune Signaling Pathways

Upon recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), intracellular signaling cascades are initiated to orchestrate immune responses. These pathways primarily involve adaptor proteins that transduce signals from the receptor to downstream effectors, culminating in the activation of transcription factors and production of inflammatory mediators. The MyD88-dependent pathway is a central mechanism in TLR signaling, engaged by most TLRs except TLR3. Upon PAMP binding, TLRs recruit the adaptor protein MyD88, which forms a complex known as the myddosome with interleukin-1 receptor-associated kinases (IRAK4, IRAK1/2) and TNF receptor-associated factor 6 (TRAF6). This complex activates the (IKK) complex, leading to the nuclear translocation of and activation of mitogen-activated protein kinases (MAPKs), such as JNK and p38. Consequently, these transcription factors drive the expression of proinflammatory cytokines, including TNF-α and IL-6. In contrast, the TRIF-dependent pathway is utilized by TLR3 and endosomal TLR4 signaling. Ligand engagement recruits the adaptor protein TRIF (also known as TICAM1), often via the intermediary TICAM2 (), which interacts with TRAF3 and receptor-interacting protein kinase 1 (RIP1). This leads to the activation of (TBK1) and IKKε, phosphorylating interferon regulatory factors and IRF7. Phosphorylated IRFs translocate to the nucleus, inducing the production of type I s, which are crucial for antiviral immunity. The represents another key pathway activated by certain PAMPs, particularly through a two-signal process. The first signal, often from TLRs recognizing PAMPs like (LPS), primes the pathway by upregulating and pro-IL-1β expression via . The second signal, triggered by additional stimuli such as potassium efflux or , induces NLRP3 oligomerization, recruitment of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), and of caspase-1. Active caspase-1 then cleaves pro-IL-1β to its mature form, promoting its and inflammatory responses, while also initiating through gasdermin D. Key components include NLRP3 as the sensor, ASC as the adaptor, and caspase-1 as the effector, with NEK7 modulating assembly. To prevent excessive , these pathways are tightly regulated by mechanisms. Phosphatases, such as Src homology 2 domain-containing phosphatases (SHP-1/SHP-2), dephosphorylate key signaling molecules like IRAKs and TBK1, thereby attenuating , MAPK, and IRF activation. Decoy receptors, including CEACAM1 and soluble TLR homologs like RP105, sequester PAMPs or compete for adaptor recruitment, limiting signal initiation and downstream production such as TNF-α and IL-6. These regulators maintain immune and mitigate risks of chronic or .

Role in Immunity

Innate Immune Activation

Recognition of pathogen-associated molecular patterns (PAMPs) by receptors (PRRs) initiates signaling cascades that rapidly mobilize innate immune defenses. This activates key effector cells, including macrophages, dendritic cells, and neutrophils, to mount immediate antimicrobial responses. Following in macrophages and neutrophils, PRRs such as (TLR2) are recruited to phagosomal membranes to facilitate intracellular degradation and trigger inflammatory responses. Concurrently, these cells produce (ROS) through NADPH oxidase activation, which generates oxidative bursts to damage microbial components and support killing. Dendritic cells and macrophages further release via TLR-mediated transcription of genes involved in innate antimicrobial activity. The inflammatory cascade is a hallmark of PAMP-induced , amplifying the response through soluble mediators. PRR signaling triggers the production and secretion of , including IL-8 and , which recruit additional neutrophils, monocytes, and other immune cells to the infection site, establishing a coordinated inflammatory focus. Complement activation is also initiated, often via PRR-associated molecules like mannose-binding lectin (MBL), leading to opsonization of pathogens and enhanced while generating anaphylatoxins that promote local inflammation. Systemically, cytokines such as IL-1 and TNF-α induce fever by acting on the , elevating body temperature to inhibit microbial replication and enhance immune cell function. PAMP recognition further strengthens host barriers to limit pathogen dissemination. In mucosal tissues, PRR activation upregulates epithelial integrity and secretory responses, such as increased mucin production and IgA secretion, thereby reinforcing mucosal immunity against invading microbes. At endothelial sites, signaling through receptors like TLR4 and NOD1 promotes the expression of tight junction proteins, such as claudins and occludins, which tighten intercellular barriers and prevent pathogen extravasation into deeper tissues. These enhancements collectively provide a rapid, non-specific frontline defense.

Influence on Adaptive Immunity

Pathogen-associated molecular patterns (PAMPs) detected by pattern recognition receptors (PRRs) on antigen-presenting cells, particularly dendritic cells (DCs), critically bridge innate and adaptive immunity by promoting the maturation and activation of DCs for effective T-cell priming. Upon PAMP recognition, DCs upregulate ( molecules and co-stimulatory molecules such as and , which provide the necessary signals for naïve T-cell activation and differentiation. This enhanced is essential for initiating antigen-specific adaptive responses, with conventional DC1 (cDC1) subsets specializing in of exogenous antigens on to prime + T cells. The cytokine milieu shaped by PAMP-induced signaling further directs adaptive immune polarization toward protective effector responses. Activation of PRRs like Toll-like receptors (TLRs) on DCs triggers production of IL-12, promoting Th1 differentiation and cytotoxic T-cell responses against intracellular pathogens, while IL-6, IL-23, and IL-1β drive Th17 polarization to enhance mucosal immunity and neutrophil recruitment. activation downstream of certain PRRs synergizes with TLR signaling to amplify IL-1β and IL-18 secretion, reinforcing Th17 and Th1 biases that bolster production and cell-mediated . PAMPs also contribute to long-term adaptive formation through both indirect epigenetic modifications in innate cells and direct effects on B cells. In innate immune cells such as monocytes and macrophages, PAMP exposure induces trained immunity via epigenetic reprogramming, including modifications and enhanced accessibility at inflammatory gene promoters, leading to heightened responsiveness that supports sustained adaptive priming upon re-exposure. This trained state in innate cells indirectly enhances adaptive by improving DC function and support for T- and B-cell responses. Directly, B cells express PRRs like TLR7 and TLR9; co-ligation with B-cell receptors by PAMPs promotes class-switch recombination, differentiation, and high-affinity production, essential for humoral . B cells require ongoing TLR signaling to maintain long-term serological and rapid recall responses.

Types of PAMPs

Bacterial PAMPs

Bacterial pathogen-associated molecular patterns (PAMPs) are conserved molecular structures unique to prokaryotic cells that serve as signals for host immune recognition, primarily through receptors (PRRs) such as Toll-like receptors (TLRs). These patterns are derived from essential bacterial components like elements and proteins, enabling the to distinguish bacterial invaders from host cells. In , (LPS), also known as endotoxin, is a major PAMP embedded in the outer membrane. The bioactive component of LPS is , a phosphorylated acylated with fatty acids, which is specifically recognized by TLR4 in complex with MD-2 and CD14. This recognition initiates immune signaling without delving into downstream pathways. Gram-positive bacteria feature distinct PAMPs in their thick layer and teichoic acids. , a of N-acetylglucosamine and N-acetylmuramic acid cross-linked by bridges, is detected by TLR2 and intracellular receptors. Lipoteichoic acid (LTA), an amphipathic glycerol anchored to the membrane and extending through the , is primarily sensed by TLR2. Certain bacterial PAMPs are shared across both Gram-negative and Gram-positive species. Flagellin, the structural protein forming the filament of bacterial flagella essential for motility, acts as a ligand for TLR5. Bacterial DNA, characterized by unmethylated CpG motifs, is recognized by endosomal TLR9. Additional variations include outer membrane porins from Gram-negative bacteria, which are beta-barrel proteins forming channels and recognized by TLR2, and components of pili or fimbriae, such as pilin proteins, which contribute to adhesion and can engage TLRs indirectly through associated motifs. These structures highlight the diversity of bacterial PAMPs while maintaining conserved features for reliable detection.

Viral PAMPs

Viral pathogen-associated molecular patterns (PAMPs) are molecular signatures derived from viral components that trigger innate immune recognition, primarily through s and structural proteins unique to and assembly. Unlike bacterial PAMPs, which often involve structures, viral PAMPs emphasize intracellular nucleic acid intermediates and envelope elements that distinguish viral infection from host cellular processes. These patterns are detected by specific receptors (PRRs), enabling rapid antiviral responses. Nucleic acid-based viral PAMPs constitute the majority of recognized signatures, with double-stranded (dsRNA) serving as a prominent example generated during . DsRNA, often produced as replication intermediates, is sensed by retinoic acid-inducible gene I (RIG-I) for shorter fragments bearing 5'-triphosphate ends and by differentiation-associated protein (MDA5) for longer dsRNA molecules, both cytosolic sensors that initiate production. Intracellular detection by RIG-I-like receptors (RLRs) exemplifies this process, highlighting the host's ability to monitor viral synthesis. Single-stranded (ssRNA) from viruses, such as those with positive-sense genomes, is recognized endosomally by Toll-like receptors 7 and 8 (TLR7/8), which bind uridine- or guanosine-rich motifs to activate inflammatory and pathways. Viral DNA, exemplified by herpes simplex virus 1 (HSV-1) genomes, is detected in the by cyclic GMP-AMP synthase (cGAS), which catalyzes the production of the second messenger 2'3'-cGAMP to activate the stimulator of interferon genes (STING) pathway, leading to type I induction. Protein-based viral PAMPs, particularly envelope glycoproteins, provide additional extracellular cues for immune detection. These glycoproteins, integral to viral entry and budding, are recognized by surface PRRs such as TLR2 and TLR4, often in heterodimeric complexes. For instance, the envelope protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages TLR2 to drive proinflammatory cytokine release, independent of viral replication. Similarly, the envelope glycoprotein of Kaposi's sarcoma-associated herpesvirus activates TLR4 on lymphatic endothelial cells, promoting antiviral signaling. Replication intermediates like unmethylated CpG dinucleotides, prevalent in viral DNA genomes due to the absence of host-like methylation, are sensed by endosomal TLR9, distinguishing foreign DNA from self and amplifying immune activation against DNA viruses.

Fungal and Parasitic PAMPs

Fungal pathogens present a variety of components as PAMPs that are recognized by host immune receptors, primarily receptors (CLRs). Beta-1,3-glucans, abundant in the fungal , serve as key ligands for the receptor Dectin-1, triggering immune responses such as production and in macrophages and dendritic cells. This recognition is essential for controlling infections like those caused by , where Dectin-1 deficiency leads to heightened susceptibility. Mannans, another major fungal glycan, are detected by multiple receptors including TLR4 and Mincle, initiating signaling pathways that promote inflammation and adaptive immunity. For instance, mannosylated structures from species engage Mincle and Dectin-2 cooperatively, enhancing host defense against opportunistic fungal infections. Chitin, a structural in fungal cell walls, is recognized by various CLRs, contributing to innate immune activation against fungi such as and . This interaction drives recruitment and Th17 cell differentiation, crucial for mucosal immunity. Zymosan, derived from cell walls, acts as a complex multi-PAMP particle containing beta-glucans, mannans, and chitin, which collectively stimulate multiple pattern recognition receptors including Dectin-1, TLR2, and the . Exposure to zymosan induces robust cytokine release, such as IL-1β, modeling the inflammatory response to intact fungal particles in host tissues. Parasitic protozoans, being eukaryotic, share some glycan-based PAMPs with fungi but exhibit unique structures tailored to their life cycles. Glycosylphosphatidylinositol (GPI) anchors, glycolipids anchoring surface proteins, are prominent PAMPs in parasites like Plasmodium falciparum and Trypanosoma species, primarily activating TLR2 and TLR4 to elicit proinflammatory cytokines such as TNF-α. These anchors vary in glycosylation, enabling parasite-specific immune evasion or hyperactivation, as seen in malaria where GPI triggers endothelial inflammation. Hemozoin, the crystalline pigment formed by Plasmodium during hemoglobin digestion, functions as a PAMP by activating the NLRP3 inflammasome in macrophages, leading to IL-1β secretion and contributing to malaria-associated immunopathology. Profilin, an actin-binding protein from Toxoplasma gondii, is a specific ligand for TLR11, driving IL-12 production in dendritic cells and essential for early resistance to toxoplasmosis. This recognition promotes IFN-γ-dependent immunity, highlighting profilin's role in bridging innate and adaptive responses. Eukaryotic pathogens like fungi and parasites share features such as phosphorylated glycans and mucins, which modulate immune detection. Phosphorylated glycans on parasite surfaces can engage CLR family members, fine-tuning inflammatory signals without direct TLR activation. Mucin-like glycoproteins, abundant in trypanosomatids, serve as PAMPs that interact with host , promoting while potentially masking other antigens to evade immunity.

Special Cases and Variations

Mycobacterial PAMPs

Mycobacteria, exemplified by Mycobacterium tuberculosis, feature a distinctive cell wall architecture characterized by an exceptionally high lipid content, which sets them apart from typical bacteria lacking lipopolysaccharide. This lipid-rich envelope harbors unique pathogen-associated molecular patterns (PAMPs) that interact with host pattern recognition receptors, facilitating intracellular survival. Prominent among these are lipoarabinomannan (LAM) and phosphatidylinositol mannosides (PIMs), glycolipids integral to the cell wall. LAM, a phosphatidylinositol-anchored polysaccharide, and its mannose-capped variant (ManLAM) are primarily recognized by Toll-like receptor 2 (TLR2) on innate immune cells, triggering proinflammatory signaling. Additionally, ManLAM engages C-type lectin receptors (CLRs) such as Dectin-2, which mediates antifungal-like responses but in this context promotes mycobacterial uptake and modulation of host defenses. PIMs, ranging from di- to hexa-mannosylated forms, similarly bind TLR2 to elicit cytokine production while interacting with CLRs like DC-SIGN, influencing dendritic cell function and T cell priming. Mycolic acids, exceptionally long-chain (C70–C90) α-branched β-hydroxy fatty acids, constitute a major lipid component of the mycobacterial outer membrane, covalently linked to and forming the mycolate layer. These acids are recognized by the CLR Mincle, particularly when incorporated into , activating Syk-dependent signaling that can drive both protective formation and immune evasion through dampened activation. The abundance of these lipids enables mycobacteria to persist within by altering membrane fluidity and evading lysosomal fusion. A key evasion mechanism involves ManLAM, which inhibits phagosome maturation by blocking the recruitment of Rab5 and class III phosphatidylinositol 3-kinase, thereby preventing acidification and acquisition of lysosomal hydrolases. This arrest allows intracellular replication, underscoring the role of mycobacterial PAMPs in chronic infection.

Emerging Patterns in Biofilms

Biofilm-associated molecular patterns (BAMPs) represent a subset of pathogen-associated molecular patterns (PAMPs) that emerge specifically within microbial biofilms, distinguishing them from those in free-floating planktonic cells through their structural and functional context. These patterns are primarily components of the extracellular polymeric substances (EPS) matrix, which constitutes up to 90% of a biofilm's biomass and includes polysaccharides like alginate, proteins, and extracellular DNA (eDNA). In Pseudomonas aeruginosa biofilms, alginate serves as a dominant EPS component, forming a protective gel-like structure that encapsulates bacterial communities and modulates host immune interactions. eDNA, released via bacterial lysis or active secretion, contributes to biofilm integrity by facilitating adhesion and structural stability, while also acting as a signaling molecule. Recognition of BAMPs by the host immune system occurs through pattern recognition receptors (PRRs), with eDNA in biofilms triggering responses via (TLR9) and NOD-like receptors (NLRs), leading to activation and production. Similarly, alginate and other EPS elements can engage surface TLRs, although the matrix often attenuates direct recognition by shielding underlying PAMPs, thereby promoting immune evasion. NLRs, such as , detect intracellular signals from biofilm-derived components, contributing to IL-1β secretion and sustained inflammatory responses. This differential recognition highlights how biofilms transform standard PAMPs into more persistent threats, overlapping briefly with planktonic forms but amplified by matrix confinement. Biofilms enhance persistence by amplifying PAMP exposure through quorum-sensing (QS) molecules, such as autoinducers (e.g., N-acyl homoserine lactones in P. aeruginosa), which coordinate community behaviors and indirectly trigger chronic . These autoinducers not only regulate biofilm maturation but also act as low-molecular-weight signals that mimic or enhance PAMP effects, sustaining recruitment and tissue damage without resolving the infection. In chronic settings, this QS-driven amplification leads to persistent low-grade , as seen in lung infections where dispersal signals paradoxically heighten host responses. Post-2020 research has illuminated BAMPs' roles in device-related infections, particularly those involving P. aeruginosa alginate, which forms resilient on indwelling medical devices like catheters and implants, complicating eradication and contributing to up to 80% of microbial infections associated with such devices. Studies from 2021 onward demonstrate that alginate matrices in these elicit muted but prolonged innate responses, with eDNA and driving NLR-mediated in macrophages, exacerbating implant failure and recurrent infections. For instance, alginate overproduction in clinical isolates has been linked to reduced TLR signaling efficiency, fostering chronic device-associated and prompting exploration of matrix-degrading enzymes as adjunct therapies. These insights underscore BAMPs as critical targets for disrupting persistence in biomedical contexts.

Historical Development

Conceptual Foundations

In the late 19th century, early observations of bacterial components triggering immune responses laid crucial groundwork for understanding innate defenses. Richard Pfeiffer, working with , introduced the concept of endotoxins in 1892, describing them as heat-stable toxins derived from bacteria such as that induced fever and other pathophysiological effects in hosts without eliciting neutralizing antibodies. These findings highlighted how specific microbial substances could provoke non-specific inflammatory reactions, foreshadowing the recognition of conserved features in immunity. Pioneering work in innate immunity further emphasized cellular mechanisms of recognition. In the , Elie Metchnikoff proposed the theory after observing mobile cells in larvae engulfing foreign particles, positing that served as a primary, non-specific defense against microbes through direct engulfment and destruction. This cellular theory of immunity contrasted with prevailing humoral views and implied an evolutionarily ancient system for broad microbial detection, independent of prior exposure. By the 1970s and 1980s, immunological research predominantly emphasized adaptive immunity, focusing on T and responses and specificity, which marginalized studies of germline-encoded innate defenses like and endotoxin responses. This adaptive-centric paradigm overlooked the foundational role of innate mechanisms in initiating and shaping immune reactions, creating a conceptual gap that early ideas from Pfeiffer and Metchnikoff had begun to address. These pre-1989 insights provided the intellectual context for later hypotheses on in innate immunity.

Key Discoveries and Milestones

In 1989, Charles A. Janeway Jr. proposed the concept of pattern recognition receptors (PRRs) that detect exogenous molecular patterns from pathogens, distinguishing them from , during his introductory address at the Cold Spring Harbor Symposium on Quantitative Biology. This theoretical framework laid the groundwork for identifying specific receptors that recognize pathogen-associated molecular patterns (PAMPs), shifting focus from adaptive to innate immunity mechanisms. The 1990s marked the experimental validation of Janeway's ideas with the discovery of Toll-like receptors (TLRs). In 1997, and Janeway identified a human homolog of the Toll protein, TLR4, which signals the activation of adaptive immunity upon microbial stimulation, confirming its role as a PRR for bacterial components. This breakthrough was followed in 1998 by the linkage of TLR4 to (LPS) recognition; genetic studies in mice revealed that mutations in the Tlr4 gene rendered animals hyporesponsive to LPS, establishing TLR4 as the primary receptor for this bacterial PAMP. The 2000s expanded PAMP recognition to viral pathogens through the identification of cytoplasmic RNA sensors. In 2004, researchers demonstrated that retinoic acid-inducible gene I (RIG-I), a , detects double-stranded viral RNA and triggers type I production, representing a key intracellular PRR for viral PAMPs. In the early , nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), such as NOD1 and , were identified as intracellular sensors of bacterial peptidoglycans, expanding PAMP recognition to cytosolic compartments. Concurrently, studies on fungal PAMPs advanced with the 2001 identification of Dectin-1 as a receptor (CLR) that binds β-glucans from fungal cell walls, initiating antifungal responses; subsequent work in the and elucidated its signaling pathways and role in broader CLR-mediated immunity. Research in the 2010s deepened understanding of parasitic PAMPs, particularly glycosylphosphatidylinositol (GPI) anchors. Studies showed that Plasmodium falciparum GPI structures act as TLR2 agonists, inducing proinflammatory cytokines and contributing to malaria pathology, with structural analyses confirming their conserved motifs as immunogenic patterns across protozoan parasites. In 2025, investigations into biofilms introduced the concept of biofilm-associated molecular patterns (BAMPs), a subset of PAMPs uniquely expressed in biofilm matrices, such as modified polysaccharides and extracellular DNA in bacterial communities, which evade traditional PRR detection and promote chronic infections.

References

  1. https://www.nature.com/articles/s41392-021-00687-0
  2. https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Kaiser)/Unit_5:_Innate_Immunity/11.4:_Early_Induced_Innate_Immunity/11.3A:_Pathogen-Associated_Molecular_Patterns_(PAMPs)_and_Danger-Associated_Molecular_Patterns_(DAMPs)
  3. https://www.sciencedirect.com/topics/nursing-and-health-professions/pathogen-associated-molecular-pattern
  4. https://pubmed.ncbi.nlm.nih.gov/2700931/
  5. https://www.cell.com/immunity/fulltext/S1074-7613%2809%2900242-8
  6. https://pmc.ncbi.nlm.nih.gov/articles/PMC5877582/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC7126801/
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC2668232/
  9. https://pmc.ncbi.nlm.nih.gov/articles/PMC11354642/
  10. https://pmc.ncbi.nlm.nih.gov/articles/PMC2150873/
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC4271212/
  12. https://onlinelibrary.wiley.com/doi/10.1155/2015/794143
  13. https://www.nature.com/articles/s41392-025-02264-1
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC9226403/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC3584666/
  16. https://doi.org/10.1038/44605
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC3828604/
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC4637384/
  19. https://doi.org/10.1189/jlb.1105626
  20. https://www.ncbi.nlm.nih.gov/books/NBK562910/
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC7500085/
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC3196803/
  23. https://www.sciencedirect.com/science/article/pii/S1074761324001353
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC5087274/
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC4630409/
  26. https://pmc.ncbi.nlm.nih.gov/articles/PMC3536141/
  27. https://www.sciencedirect.com/science/article/pii/S0021925820465342
  28. https://www.nature.com/articles/s41392-020-0198-7
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC8882317/
  30. https://pmc.ncbi.nlm.nih.gov/articles/PMC2698447/
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC1888731/
  32. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.812148/full
  33. https://www.sciencedirect.com/science/article/pii/S1084952117305414
  34. https://www.sciencedirect.com/science/article/pii/S1931312813001182
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC6461132/
  36. https://onlinelibrary.wiley.com/doi/10.1111/j.1462-5822.2010.01474.x
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC2742822/
  38. https://www.researchgate.net/publication/10687427_Macrophage_recognition_of_zymosan_particles
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC6305727/
  40. https://www.nature.com/articles/nri1978
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC2722371/
  42. https://pubmed.ncbi.nlm.nih.gov/18312842/
  43. https://www.science.org/doi/abs/10.1126/science.1109893
  44. https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00710/full
  45. https://journals.asm.org/doi/10.1128/iai.00304-25
  46. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.625597/full
  47. https://www.nature.com/articles/s41392-022-01056-1
  48. https://www.mdpi.com/1422-0067/22/16/9100
  49. https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2012.00062/full
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC3139209/
  51. https://www.nature.com/articles/s41522-025-00738-2
  52. https://www.nature.com/articles/mi201077
  53. https://onlinelibrary.wiley.com/doi/10.5402/2012/853123
  54. https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01582/full
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC11274200/
  56. https://www.sciencedirect.com/science/article/pii/S1286457903002624
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC10168657/
  58. https://www.sciencedirect.com/science/article/pii/S1074761324001286
  59. https://pubmed.ncbi.nlm.nih.gov/9237759/
  60. https://pubmed.ncbi.nlm.nih.gov/9768750/
  61. https://pubmed.ncbi.nlm.nih.gov/15208682/
  62. https://pubmed.ncbi.nlm.nih.gov/11329570/
  63. https://pubmed.ncbi.nlm.nih.gov/11544248/
  64. https://pubmed.ncbi.nlm.nih.gov/11544516/
  65. https://pubmed.ncbi.nlm.nih.gov/17003138/
Add your contribution
Related Hubs
User Avatar
No comments yet.