LPS

STRUCTURE (3 parts): (1) Lipid A, the toxic endotoxin component, is embedded in the outer membrane. It is a phosphorylated glucosamine disaccharide with fatty acid chains. (2) Core polysaccharide, which contains KDO (2-keto-3-deoxyoctonate). (3) O antigen (O-polysaccharide), the outermost, highly variable repeating oligosaccharide. It is the basis of serotyping (e.g., E. coli O157:H7) and is the main target of antibody responses. It is absent in Neisseria, Haemophilus, and Bordetella, which have lipooligosaccharide (LOS) instead.

PATHOPHYSIOLOGY: LPS-binding protein (LBP) in serum transfers LPS to CD14 on macrophages, monocytes, and dendritic cells. The LPS-CD14 complex binds the TLR4/MD-2 complex. Signaling through MyD88 and NF-κB causes release of proinflammatory cytokines: IL-1, IL-6, TNF-α, and IL-8 (neutrophil chemotaxis). Complement activation (alternative pathway) and Hageman factor (factor XII) activation also occur.

CLINICAL EFFECTS: Fever (IL-1, IL-6, and TNF-α act on the hypothalamus via PGE2). Hypotension and shock result from vasodilation and increased vascular permeability (NO, TNF-α, and C5a). Other effects are DIC (tissue factor expression and factor XII activation), leukopenia and then leukocytosis, hypoglycemia, and ARDS. Endotoxic (septic) shock is classically caused by gram-negative bacteremia (E. coli, Klebsiella, Pseudomonas). Gram-negative sepsis is warm and distributive early, then cold.

KEY ASSOCIATIONS: (1) Waterhouse-Friderichsen syndrome: Neisseria meningitidis meningococcemia, with bilateral adrenal hemorrhage, DIC, and shock. (2) Jarisch-Herxheimer reaction is a related cytokine-mediated reaction after antibiotics for spirochetes (it is not LPS-mediated). (3) Gram-positive bacteria lack LPS. Their analogous PAMPs are peptidoglycan and lipoteichoic acid, which act via TLR2. (4) LPS is heat-stable and is not destroyed by autoclaving. It is a poor immunogen for toxoid vaccines, unlike exotoxins. (5) Limulus amebocyte lysate assay detects endotoxin. (6) Polymyxin B binds lipid A (a mechanism of action). Resistance can occur via lipid A modification (mcr-1). (7) Gram-negative bacteria can release more endotoxin when killed by antibiotics, especially beta-lactams that cause lysis. (8) Endotoxin is a T-cell-independent antigen that acts as a B-cell mitogen at high doses.

COMPARISON WITH EXOTOXINS: Endotoxin is LPS (lipid A), part of the cell wall, heat-stable, weakly immunogenic, and moderately toxic (fever and shock). Exotoxins are secreted proteins, mostly heat-labile, highly immunogenic (toxoid vaccines), and highly toxic.

MNEMONIC: "LPS = Lipid A is the toxic part; O antigen is the outermost and most variable part."

Note that in other contexts LPS can also mean: lysophosphatidylserine; lipoprotein synthase; or "Lipid Peroxidation Score." In USMLE contexts it nearly always means lipopolysaccharide.