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Pathogen-associated molecular pattern

Pathogen-associated molecular patterns (PAMPs) are highly conserved molecular structures or motifs shared by diverse pathogenic microorganisms, including bacteria, viruses, fungi, and protozoa, that are essential for microbial survival and viability but absent in host cells.^[1] These patterns encompass a variety of biomolecules, such as lipopolysaccharides (LPS) from Gram-negative bacterial outer membranes, peptidoglycan and lipoteichoic acids from bacterial cell walls, flagellin from bacterial flagella, and double-stranded RNA from viral genomes.^[2] The concept of PAMPs was first articulated by immunologist Charles A. Janeway Jr. in 1989 as part of his pattern recognition hypothesis, which revolutionized understanding of innate immunity by positing that germline-encoded receptors could detect broad microbial signatures to bridge innate and adaptive responses.^[1] In the innate immune system, PAMPs serve as critical danger signals that alert host cells to the presence of infection, enabling rapid discrimination between self and non-self entities.^[1] They are detected by pattern recognition 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.^[1] 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).^[1] 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 NF-κB, leading to the production of pro-inflammatory cytokines (e.g., TNF-α, IL-1β), type I interferons, and chemokines.^[1] This PAMP-driven activation not only mounts immediate antimicrobial defenses, such as phagocytosis and complement activation, but also primes adaptive immunity by promoting antigen presentation and T-cell costimulation on dendritic cells.^[1] Dysregulated PAMP recognition can contribute to pathological inflammation in conditions like sepsis or autoimmune diseases, while therapeutic strategies targeting PAMPs or PRRs, such as TLR agonists, are being explored for vaccines and immunotherapies.^[1] Overall, PAMPs represent a foundational mechanism by which multicellular organisms have co-evolved with microbes to ensure survival against infectious threats.^[2]

Definition and Properties

Definition

Pathogen-associated molecular patterns (PAMPs) are conserved molecular motifs or structures that are characteristic of microbial pathogens, including bacteria, viruses, fungi, and parasites, and are typically absent from healthy host cells.^[1] These patterns represent essential components of pathogens that enable the host innate immune system to distinguish between self and non-self entities.^[3] The concept of PAMPs was introduced by Charles A. Janeway Jr. in 1989, who proposed that the innate immune system relies on the recognition of such shared microbial patterns to mount rapid defensive responses.^[4] 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 pathogen classes, which stems from their critical role in pathogen survival and replication, making them indispensable and thus infrequently altered by evolutionary pressures.^[1] 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 pathogen.^[5] This recognition occurs through pattern recognition receptors (PRRs) expressed on immune and non-immune cells.^[4]

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 polysaccharides, lipids like lipoproteins, proteins exemplified by flagellin, and nucleic acids such as unmethylated CpG DNA.^[1] This diversity allows PAMPs to serve as reliable indicators of microbial presence across various pathogen types.^[6] Functionally, PAMPs are typically surface-exposed or secreted components of microbes that remain invariant under evolutionary pressures, as alterations would compromise pathogen survival.^[7] Their conservation enables them to elicit rapid, non-specific immune responses in hosts, activating innate defenses without prior exposure to the pathogen.^[8] From an evolutionary standpoint, PAMPs embody ancient, conserved microbial features critical for pathogen fitness, such as essential metabolic or structural roles, which have persisted due to their indispensability.^[9] This retention facilitates broad-spectrum recognition by host immune systems across diverse species, providing an effective first line of defense against infection.^[10] In contrast, damage-associated molecular patterns (DAMPs) are endogenous host-derived molecules released during cellular stress or damage.^[11]

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.^[1] The Toll-like receptor (TLR) family represents one of the most well-characterized PRR classes, originally discovered as mammalian homologs of the Drosophila 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 ligand 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 lipopolysaccharide (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 RNA (TLR3) and unmethylated CpG DNA (TLR9), facilitating pathogen surveillance during phagocytosis or endocytosis. This compartmentalization ensures TLRs probe both external and internalized threats with high specificity.^[1]^[12] 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 cell wall fragments. For instance, NOD1 detects γ-D-glutamyl-diaminopimelic acid-containing peptidoglycans prevalent in Gram-negative bacteria, 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.^[1]^[12] 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 mannose receptor and DC-SIGN bind mannose and fucose residues on microbial surfaces, while others such as Dectin-1, discovered as a beta-glucan sensor, localize to the cell surface or endosomes to engage fungal and mycobacterial polysaccharides. Dectin-1 exemplifies CLR specificity with its recognition of β-1,3-glucans, a structural motif 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.^[1]^[12] RIG-I-like receptors (RLRs), including RIG-I, MDA5, 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 MDA5 recognizes longer double-stranded RNAs, such as those produced during picornavirus replication, providing complementary coverage of viral replication strategies. Their cytoplasmic localization positions RLRs as key detectors of cytosolic viral invasion, with ligand specificity dictated by RNA structure and modification status.^[1]^[12] 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 C-type lectin domains that oligomerize into multimeric structures for enhanced avidity. MBL binds mannose, fucose, and N-acetylglucosamine on pathogen 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 pathogen classification and immune priming.^[1]^[12]

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.^[13] 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 IκB kinase (IKK) complex, leading to the nuclear translocation of NF-κB 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.^[13] 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 (TRAM), which interacts with TRAF3 and receptor-interacting protein kinase 1 (RIP1). This leads to the activation of TANK-binding kinase 1 (TBK1) and IKKε, phosphorylating interferon regulatory factors IRF3 and IRF7. Phosphorylated IRFs translocate to the nucleus, inducing the production of type I interferons, which are crucial for antiviral immunity.^[13] The NLRP3 inflammasome represents another key pathway activated by certain PAMPs, particularly through a two-signal process. The first signal, often from TLRs recognizing PAMPs like lipopolysaccharide (LPS), primes the pathway by upregulating NLRP3 and pro-IL-1β expression via NF-κB. The second signal, triggered by additional stimuli such as potassium efflux or reactive oxygen species, induces NLRP3 oligomerization, recruitment of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), and activation of caspase-1. Active caspase-1 then cleaves pro-IL-1β to its mature form, promoting its secretion and inflammatory responses, while also initiating pyroptosis through gasdermin D. Key components include NLRP3 as the sensor, ASC as the adaptor, and caspase-1 as the effector, with NEK7 modulating assembly.^[14] To prevent excessive inflammation, these pathways are tightly regulated by negative feedback mechanisms. Phosphatases, such as Src homology 2 domain-containing phosphatases (SHP-1/SHP-2), dephosphorylate key signaling molecules like IRAKs and TBK1, thereby attenuating NF-κB, 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 cytokine production such as TNF-α and IL-6. These regulators maintain immune homeostasis and mitigate risks of chronic inflammation or autoimmunity.^[13]^[15]

Role in Immunity

Innate Immune Activation

Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) initiates signaling cascades that rapidly mobilize innate immune defenses. This process activates key effector cells, including macrophages, dendritic cells, and neutrophils, to mount immediate antimicrobial responses. Following phagocytosis in macrophages and neutrophils, PRRs such as Toll-like receptor 2 (TLR2) are recruited to phagosomal membranes to facilitate intracellular degradation and trigger inflammatory responses.^[16] Concurrently, these cells produce reactive oxygen species (ROS) through NADPH oxidase activation, which generates oxidative bursts to damage microbial components and support killing.^[17] Dendritic cells and macrophages further release antimicrobial peptides via TLR-mediated transcription of genes involved in innate antimicrobial activity.^[18] The inflammatory cascade is a hallmark of PAMP-induced activation, amplifying the response through soluble mediators. PRR signaling triggers the production and secretion of chemokines, including IL-8 and CCL2, which recruit additional neutrophils, monocytes, and other immune cells to the infection site, establishing a coordinated inflammatory focus.^[19] Complement activation is also initiated, often via PRR-associated molecules like mannose-binding lectin (MBL), leading to opsonization of pathogens and enhanced phagocytosis while generating anaphylatoxins that promote local inflammation.^[1] Systemically, cytokines such as IL-1 and TNF-α induce fever by acting on the hypothalamus, elevating body temperature to inhibit microbial replication and enhance immune cell function.^[20] 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^[21] and IgA secretion,^[22] 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.^[1] 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 major histocompatibility complex (MHC) class II molecules and co-stimulatory molecules such as CD80 and CD86, which provide the necessary signals for naïve T-cell activation and differentiation.^[23] This enhanced antigen presentation is essential for initiating antigen-specific adaptive responses, with conventional DC1 (cDC1) subsets specializing in cross-presentation of exogenous antigens on MHC class I to prime CD8+ T cells.^[23] 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.^[23] Inflammasome activation downstream of certain PRRs synergizes with TLR signaling to amplify IL-1β and IL-18 secretion, reinforcing Th17 and Th1 biases that bolster antibody production and cell-mediated cytotoxicity.^[23] PAMPs also contribute to long-term adaptive memory 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 histone modifications and enhanced chromatin accessibility at inflammatory gene promoters, leading to heightened responsiveness that supports sustained adaptive priming upon re-exposure.^[24] This trained state in innate cells indirectly enhances adaptive memory by improving DC function and cytokine support for T- and B-cell responses.^[24] Directly, B cells express PRRs like TLR7 and TLR9; co-ligation with B-cell receptors by PAMPs promotes class-switch recombination, plasma cell differentiation, and high-affinity antibody production, essential for humoral memory.^[23] Memory B cells require ongoing TLR signaling to maintain long-term serological memory and rapid recall responses.^[23]

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 pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs).^[1] These patterns are derived from essential bacterial components like cell wall elements and motility proteins, enabling the innate immune system to distinguish bacterial invaders from host cells.^[25] In Gram-negative bacteria, lipopolysaccharide (LPS), also known as endotoxin, is a major PAMP embedded in the outer membrane. The bioactive component of LPS is lipid A, a phosphorylated glucosamine disaccharide acylated with fatty acids, which is specifically recognized by TLR4 in complex with MD-2 and CD14.^[1] This recognition initiates immune signaling without delving into downstream pathways.^[25] Gram-positive bacteria feature distinct PAMPs in their thick peptidoglycan layer and cell wall teichoic acids. Peptidoglycan, a polymer of N-acetylglucosamine and N-acetylmuramic acid cross-linked by peptide bridges, is detected by TLR2 and intracellular NOD2 receptors.^[1] Lipoteichoic acid (LTA), an amphipathic glycerol phosphate polymer anchored to the membrane and extending through the peptidoglycan, is primarily sensed by TLR2.^[25] 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.^[1] Bacterial DNA, characterized by unmethylated CpG motifs, is recognized by endosomal TLR9.^[25] Additional variations include outer membrane porins from Gram-negative bacteria, which are beta-barrel proteins forming channels and recognized by TLR2,^[26] and components of pili or fimbriae, such as pilin proteins, which contribute to adhesion and can engage TLRs indirectly through associated motifs.^[27] These structures highlight the diversity of bacterial PAMPs while maintaining conserved features for reliable detection.^[1]

Viral PAMPs

Viral pathogen-associated molecular patterns (PAMPs) are molecular signatures derived from viral components that trigger innate immune recognition, primarily through nucleic acids and structural proteins unique to viral replication and assembly.^[1] Unlike bacterial PAMPs, which often involve cell wall 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 pattern recognition receptors (PRRs), enabling rapid antiviral responses.^[1] Nucleic acid-based viral PAMPs constitute the majority of recognized signatures, with double-stranded RNA (dsRNA) serving as a prominent example generated during viral replication. 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 melanoma differentiation-associated protein 5 (MDA5) for longer dsRNA molecules, both cytosolic sensors that initiate interferon production.^[1] Intracellular detection by RIG-I-like receptors (RLRs) exemplifies this process, highlighting the host's ability to monitor viral genome synthesis. Single-stranded RNA (ssRNA) from RNA 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 interferon pathways.^[1] Viral DNA, exemplified by herpes simplex virus 1 (HSV-1) genomes, is detected in the cytosol 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 interferon induction.^[28] 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.^[29] Similarly, the envelope glycoprotein of Kaposi's sarcoma-associated herpesvirus activates TLR4 on lymphatic endothelial cells, promoting antiviral signaling.^[30] 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.^[1]

Fungal and Parasitic PAMPs

Fungal pathogens present a variety of cell wall components as PAMPs that are recognized by host immune receptors, primarily C-type lectin receptors (CLRs). Beta-1,3-glucans, abundant polysaccharides in the fungal cell wall, serve as key ligands for the receptor Dectin-1, triggering antifungal immune responses such as cytokine production and phagocytosis in macrophages and dendritic cells.^[31] This recognition is essential for controlling infections like those caused by Candida albicans, where Dectin-1 deficiency leads to heightened susceptibility.^[32] Mannans, another major fungal glycan, are detected by multiple receptors including TLR4 and Mincle, initiating signaling pathways that promote inflammation and adaptive immunity.^[33] For instance, mannosylated structures from Malassezia species engage Mincle and Dectin-2 cooperatively, enhancing host defense against opportunistic fungal infections.^[34] Chitin, a structural polymer in fungal cell walls, is recognized by various CLRs, contributing to innate immune activation against fungi such as Aspergillus and Cryptococcus.^[35] This interaction drives phagocyte recruitment and Th17 cell differentiation, crucial for mucosal antifungal immunity.^[36] Zymosan, derived from yeast 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 NLRP3 inflammasome.^[37] Exposure to zymosan induces robust cytokine release, such as IL-1β, modeling the inflammatory response to intact fungal particles in host tissues.^[38] 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.^[39] These anchors vary in glycosylation, enabling parasite-specific immune evasion or hyperactivation, as seen in malaria where GPI triggers endothelial inflammation.^[40] 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.^[41] 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.^[42] This recognition promotes IFN-γ-dependent immunity, highlighting profilin's role in bridging innate and adaptive responses.^[43] 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.^[44] Mucin-like glycoproteins, abundant in trypanosomatids, serve as PAMPs that interact with host lectins, promoting phagocytosis while potentially masking other antigens to evade immunity.^[44]

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 arabinogalactan and forming the mycolate layer. These acids are recognized by the CLR Mincle, particularly when incorporated into trehalose dimycolate (cord factor), activating Syk-dependent signaling that can drive both protective granuloma formation and immune evasion through dampened macrophage activation. The abundance of these lipids enables mycobacteria to persist within macrophages 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.^[45] 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).^[46] 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.^[47] 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.^[48] Recognition of BAMPs by the host immune system occurs through pattern recognition receptors (PRRs), with eDNA in biofilms triggering responses via Toll-like receptor 9 (TLR9) and NOD-like receptors (NLRs), leading to inflammasome activation and cytokine production.^[49] 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.^[50] NLRs, such as NLRP3, detect intracellular signals from biofilm-derived components, contributing to IL-1β secretion and sustained inflammatory responses.^[51] 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 pathogen 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 inflammation.^[52] These autoinducers not only regulate biofilm maturation but also act as low-molecular-weight signals that mimic or enhance PAMP effects, sustaining neutrophil recruitment and tissue damage without resolving the infection.^[53] In chronic settings, this QS-driven amplification leads to persistent low-grade inflammation, as seen in lung infections where biofilm dispersal signals paradoxically heighten host responses.^[54] Post-2020 research has illuminated BAMPs' roles in device-related infections, particularly those involving P. aeruginosa alginate, which forms resilient biofilms on indwelling medical devices like catheters and implants, complicating eradication and contributing to up to 80% of microbial infections associated with such devices.^[55] Studies from 2021 onward demonstrate that alginate matrices in these biofilms elicit muted but prolonged innate responses, with eDNA and polysaccharides driving NLR-mediated pyroptosis in macrophages, exacerbating implant failure and recurrent infections.^[46] For instance, alginate overproduction in clinical isolates has been linked to reduced TLR signaling efficiency, fostering chronic device-associated osteomyelitis and prompting exploration of matrix-degrading enzymes as adjunct therapies.^[51] These insights underscore BAMPs as critical targets for disrupting biofilm persistence in biomedical contexts.^[45]

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 Robert Koch, introduced the concept of endotoxins in 1892, describing them as heat-stable toxins derived from bacteria such as Vibrio cholerae that induced fever and other pathophysiological effects in hosts without eliciting neutralizing antibodies.^[56] These findings highlighted how specific microbial substances could provoke non-specific inflammatory reactions, foreshadowing the recognition of conserved pathogen features in immunity.^[57] Pioneering work in innate immunity further emphasized cellular mechanisms of pathogen recognition. In the 1880s, Elie Metchnikoff proposed the phagocytosis theory after observing mobile cells in starfish larvae engulfing foreign particles, positing that phagocytes served as a primary, non-specific defense against microbes through direct engulfment and destruction.^[57] This cellular theory of immunity contrasted with prevailing humoral views and implied an evolutionarily ancient system for broad microbial detection, independent of prior exposure.^[58] By the 1970s and 1980s, immunological research predominantly emphasized adaptive immunity, focusing on T and B cell responses and antibody specificity, which marginalized studies of germline-encoded innate defenses like phagocytosis and endotoxin responses.^[58] 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 pattern recognition in innate immunity.^[57]

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 self, during his introductory address at the Cold Spring Harbor Symposium on Quantitative Biology.^[4] 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, Ruslan Medzhitov and Janeway identified a human homolog of the Drosophila Toll protein, TLR4, which signals the activation of adaptive immunity upon microbial stimulation, confirming its role as a PRR for bacterial components.^[59] This breakthrough was followed in 1998 by the linkage of TLR4 to lipopolysaccharide (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.^[60] 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 RNA helicase, detects double-stranded viral RNA and triggers type I interferon production, representing a key intracellular PRR for viral PAMPs.^[61] In the early 2000s, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), such as NOD1 and NOD2, were identified as intracellular sensors of bacterial peptidoglycans, expanding PAMP recognition to cytosolic compartments.^[62]^[63] Concurrently, studies on fungal PAMPs advanced with the 2001 identification of Dectin-1 as a C-type lectin receptor (CLR) that binds β-glucans from fungal cell walls, initiating antifungal responses; subsequent work in the 2000s and 2010s elucidated its signaling pathways and role in broader CLR-mediated immunity.^[64] 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.^[65] 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.^[45]

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Jun 10, 2022 · Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory ...
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https://doi.org/10.1038/44605
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https://pmc.ncbi.nlm.nih.gov/articles/PMC3828604/
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https://pmc.ncbi.nlm.nih.gov/articles/PMC4637384/
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https://doi.org/10.1189/jlb.1105626
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Control of adaptive immunity by pattern recognition receptors
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Trained immunity: a program of innate immune memory in health ...
Trained immunity is orchestrated by epigenetic reprogramming, broadly defined as sustained changes in gene expression and cell physiology that do not involve ...
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An Overview of Pathogen Recognition Receptors for Innate ... - NIH
Pathogen recognition receptors (PRRs) are a class of germ line-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs).
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Dectin-1 is required for β-glucan recognition and control of fungal ...
Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans.Missing: review | Show results with:review
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Dectin-1 Signaling Update: New Perspectives for Trained Immunity
Structurally, Dectin-1 has a single CRD that specifically recognizes polysaccharides defined as β- (1 → 3)/(1 → 6) – glucans, initially described to be present ...
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Pattern recognition receptors in fungal immunity - ScienceDirect.com
Dectin-2 and Mincle bind fungal cell wall mannans (Table 1), and interaction of Mcl with Dectin-2 increased recognition of α-mannans. However distinct ...
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Identification of Distinct Ligands for the C-type Lectin Receptors ...
Apr 17, 2013 · Here we report that Malassezia, an opportunistic skin fungal pathogen, is cooperatively recognized by Mincle and Dectin-2 through distinct ligands.Article · Results · Mincle Is Necessary And...
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Pattern recognition receptors in fungal immunity - PMC
These PRRs sense various fungal cell wall components such as β-glucans, mannans, mannoproteins and chitin as well as fungal-derived RNA and unmethylated DNA ( ...
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Fungal Zymosan and Mannan Activate the Cryopyrin Inflammasome
These results demonstrate that the conserved fungal components zymosan and mannan require ASC and Cryopyrin for caspase-1 activation and IL-1β secretion.Missing: multi- particle
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Macrophage recognition of zymosan particles - ResearchGate
Aug 6, 2025 · Zymosan particles have served as a model for recognition of microbes by the innate immune system for over 50 years.Missing: multi- | Show results with:multi-
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Parasite Recognition and Signaling Mechanisms in Innate Immune ...
The biosynthesis of GPI is essential for the survival of parasites as GPI anchors ... Thus, malaria parasite GPI is mainly a TLR2-activating PAMP. Table 2. Innate ...Liver Stage Parasite Sensing · Malarial Pamps · Phagocytosis- And...
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Protozoan encounters with Toll-like receptor signalling pathways
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Malarial Hemozoin Activates the NLRP3 Inflammasome through Lyn ...
Aug 21, 2009 · Here we provide the first demonstration that the malaria pigment hemozoin (Hz) can also activate the NLRP3 inflammasome.
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Toxoplasma profilin is essential for host cell invasion and TLR11 ...
Feb 14, 2008 · Furthermore, parasites lacking profilin are unable to induce TLR11-dependent production in vitro and in vivo of the defensive host cytokine ...
[35]
TLR11 Activation of Dendritic Cells by a Protozoan Profilin ... - Science
T. gondii profilin activates DCs through TLR11 and is the first chemically defined ligand for this TLR. Moreover, TLR11 is required in vivo for parasite-induced ...
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Mucins and Pathogenic Mucin-Like Molecules Are ... - Frontiers
Mucins and mucin-like molecules derived from pathogens are potential diagnostic markers and targets for therapeutic agents.
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Biofilm-associated molecular patterns: BAMPs | Infection and Immunity
Aug 21, 2025 · With this concept of BAMPs, we aim to establish a clearer insight into biofilm-associated molecular patterns and their role in distinguishing ...
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Immune Responses to Pseudomonas aeruginosa Biofilm Infections
One group of TLRs is expressed on the surface of host cells where they mainly recognize microbial membrane components including lipoproteins, proteins and ...Missing: NLR | Show results with:NLR
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Pseudomonas aeruginosa: pathogenesis, virulence factors ... - Nature
Jun 25, 2022 · Correspondingly, TLRs are capable of recognizing different pathogen-associated molecular patterns found in P. aeruginosa. LPS is a major ...<|separator|>
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Extracellular DNA (eDNA). A Major Ubiquitous Element of ... - MDPI
Biofilm formation is being universally recognized as a ... Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition.Missing: PAMPs | Show results with:PAMPs<|separator|>
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Deciphering mechanisms of staphylococcal biofilm evasion of host ...
However, it is well recognized that extracellular DNA (eDNA) can also trigger TLR9-dependent activation, which is relevant to biofilms due to the extensive ...
[42]
Dampening Host Sensing and Avoiding Recognition in ...
The loss or modification of several PAMPs (flagellin, LPS, and PGN) lead to reduced recognition by TLRs and NLRs although components of the alginate capsule can ...
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Immune system dynamics in response to Pseudomonas aeruginosa ...
Jun 12, 2025 · Chronic inflammation triggered by persistent biofilms can result in increasing tissue damage and organ failure, as seen in the lungs of ...
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To be or not to be a pathogen: that is the mucosally relevant question
Dec 8, 2010 · Controlled amounts of bacterial pathogen-associated molecular motifs (PAMPs) and equivalent molecules such as quorum-sensing autoinducers (QSMs) ...Hypothesis 1 · Hypothesis 2 · Hypothesis 3
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Host Defence against Bacterial Biofilms: “Mission Impossible”?
Nov 5, 2012 · As described above, quorum-sensing molecules are produced by bacteria as autoinducers and participate in biofilm formation. P. aeruginosa ...
[46]
Can Biofilm Be Reversed Through Quorum Sensing in ... - Frontiers
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Medical Device-Associated Infections Caused by Biofilm-Forming ...
Jul 4, 2024 · In the present review, we address numerous pathogenic microbes that form biofilms on the surfaces of biomedical devices.
[48]
Richard Pfeiffer and Alexandre Besredka: creators of the concept of ...
Richard Pfeiffer, working with Robert Koch in Berlin, intellectually and experimentally conceived the concept of endotoxin as a heat-stable bacterial poison.
[49]
A short history of innate immunity - PMC - PubMed Central
Innate immunity is the first line of defense, studied since the 19th century, and developed earlier than adaptive immunity, appearing around 1 billion years ...
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The conceptual foundations of innate immunity: Taking stock 30 ...
Apr 9, 2024 · Structural molecules specific to a class of microbes (PAMPs/MAMPs) are recognized by host pattern recognition receptors (PRRs), which trigger ...
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A human homologue of the Drosophila Toll protein signals activation ...
We report here the cloning and characterization of a human homologue of the Drosophila toll protein (Toll) which has been shown to induce the innate immune ...Missing: discovery 1996
[52]
Immune recognition. A new receptor for beta-glucans - PubMed
Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of beta-glucans.