Role of Peptidoglycan (PGN) and LTA

Peptidoglycan (PGN), a key structural component of bacterial cell walls, is a critical activator of both TLR2 and NOD receptors. The composition and structure of PGN differ among Gram-positive, Gram-negative, and mycobacteria, influencing how the immune system detects and responds to bacterial infections. TLR2 is an extracellular sensor that recognizes intact PGN or PGN-derived lipoproteins, typically at the cell surface or in endosomal compartments, while NOD1 and NOD2 are intracellular receptors that detect specific PGN breakdown products within the cytosol.

Gram-positive bacteria possess a thick PGN layer composed largely of lysine-containing stem peptides. These bacteria release muramyl dipeptide (MDP), which is recognized by NOD2. In parallel, TLR2 on the cell surface binds to intact PGN fragments, lipoteichoic acid, and lipoproteins from Gram-positive organisms, driving MyD88-dependent inflammatory signaling. This dual recognition by TLR2 and NOD2 amplifies cytokine production and immune cell recruitment during infections like those caused by Staphylococcus aureus or Streptococcus pneumoniae.

Gram-negative bacteria feature a thinner PGN layer and produce diaminopimelic acid (DAP)-containing motifs. These are sensed predominantly by NOD1, which recognizes γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), triggering RIPK2-mediated NF-κB activation. Gram-negative PGN can also engage TLR2 when it is surface-exposed or released through outer membrane vesicles. Together, TLR2 and NOD1 coordinate a robust inflammatory response, particularly in infections involving Escherichia coli or Salmonella.

Mycobacteria, including Mycobacterium tuberculosis and M. leprae, have a unique, highly immunostimulatory PGN structure that includes modified muramyl dipeptides and a thick, waxy cell wall containing mycolic acids. Mycobacterial MDP potently activates NOD2 and has been shown to contribute to granulomatous inflammation and cytokine release in TB and leprosy. Additionally, TLR2 recognizes several mycobacterial ligands, including lipoproteins and PGN fragments, contributing to macrophage activation and TNFα production. Genetic polymorphisms in NOD2 and TLR2 have been associated with susceptibility to mycobacterial diseases, highlighting the importance of PGN sensing in both protective and pathological immune responses.

Lipoteichoic acid (LTA), a glycolipid anchored in the Gram-positive bacterial membrane, is a potent activator of TLR2. TLR2, particularly when dimerized with TLR6, recognizes LTA on the surface of Gram-positive bacteria, leading to downstream activation of the MyD88-dependent signaling cascade. This results in the production of key proinflammatory cytokines such as TNFα, IL-1β, and IL-6. LTA engagement also promotes neutrophil recruitment and activation, driving early innate immune responses. LTA-induced TLR2 signaling plays a central role in inflammation during infections caused by organisms like Staphylococcus aureus and Streptococcus pyogenes. Its recognition helps the host mount a rapid antimicrobial response but, when dysregulated, can contribute to septic shock, tissue damage, or chronic inflammation. Polymorphisms in TLR2 that alter LTA sensitivity have been associated with varied susceptibility to Gram-positive infections and severity of inflammatory diseases.

Both LTA and peptidoglycan (PGN) can enter systemic circulation through bacterial translocation across mucosal barriers, especially in conditions of epithelial dysfunction, dysbiosis, or infection. Translocated LTA and PGN have been detected in the blood and cerebrospinal fluid (CSF) of patients with sepsis, meningitis, inflammatory bowel disease, and neurodegenerative conditions. These circulating bacterial products can activate TLR2 on vascular endothelium, circulating immune cells, and brain-resident microglia, leading to systemic or neuroinflammation. In the CNS, blood-brain barrier disruption permits entry of LTA and PGN into the CSF, where they contribute to microglial activation and cytokine release. This mechanism is implicated in the pathogenesis of neurodegenerative and psychiatric diseases. Thus, the presence of LTA and PGN in sterile compartments like the bloodstream and CSF represents a potent trigger of immune activation via TLR2 and NOD pathways, linking microbial translocation to chronic inflammatory states. Polymorphisms in TLR2 that alter LTA sensitivity have been associated with varied susceptibility to Gram-positive infections and severity of inflammatory diseases.