LPS is a large, complex molecule found exclusively on the exterior of the outer membrane of Gram-negative bacteria, such as E. coli and Salmonella. Also known as an endotoxin, this amphipathic molecule is a major component of the bacterial surface, providing structural integrity to the cell wall. LPS functions as a permeability barrier, helping protect the bacterium from external agents like detergents, antibiotics, and bile salts. Its structure is organized into three distinct, covalently linked regions that project outward from the cell surface.
The Lipid A Anchor
The innermost section of the LPS molecule is Lipid A, which acts as the hydrophobic anchor embedding the structure into the bacterial outer membrane. Chemically, Lipid A is a phosphorylated disaccharide backbone composed of two linked glucosamine units. This backbone is decorated with multiple fatty acid chains, often six beta-hydroxy acyl chains ranging from 10 to 16 carbons in length. These hydrophobic chains moor the LPS to the lipid bilayer of the outer membrane.
The chemical arrangement of the phosphorylated glucosamine backbone and attached acyl chains is conserved among Gram-negative species. This conserved region is the primary source of the molecule’s biological activity in humans. Lipid A is recognized as the toxic component, or endotoxin, responsible for initiating the inflammatory response during Gram-negative infections. Variations in the number and length of the fatty acid chains can alter the molecule’s toxicity, influencing the severity of the host response.
The Core Oligosaccharide Segment
The Core Oligosaccharide serves as a structural bridge, connecting the embedded Lipid A anchor to the external polysaccharide chain. This intermediate segment is a non-repeating polymer, typically consisting of about ten sugar residues. Its structure is more conserved than the outermost region, especially the inner core proximal to Lipid A.
The inner core region contains unique sugars not commonly found elsewhere, such as 2-keto-3-deoxyoctulosonic acid (KDO) and L-glycero-D-manno-heptose. KDO residues are directly linked to the Lipid A backbone, forming the initial carbohydrate connection. These sugars, often substituted with non-carbohydrate components like phosphate groups, help maintain the stability of the outer membrane.
The Core Oligosaccharide extends outward to an outer core region before attaching to the final, most variable section of the LPS. This segment acts as a spacer, projecting the outermost layer away from the bacterial surface. The core structure contributes to the stability of the outer membrane and the strength of the cell wall.
The O-Antigen Outer Chain
The O-Antigen, or O-polysaccharide, is the outermost and most exposed portion of the LPS molecule, extending into the external environment. This hydrophilic structure is composed of long chains of repeating saccharide units, which can vary in length up to 50 repeats. The arrangement of these repeating units is unique to specific bacterial strains, providing a distinct surface signature.
This structural variability means the O-Antigen is used for serotyping, a method of classifying Gram-negative bacteria into serotypes based on the immune reaction they provoke. The sugar composition, which can include unusual dideoxyhexoses like abequose and tyvelose, determines the bacterium’s serological identity. The O-Antigen’s primary function is to serve as a protective, changeable surface layer that shields the bacterial cell.
By presenting a large, variable surface, the O-Antigen helps the bacterium evade recognition and destruction by the host immune system. The long polysaccharide chains impede the access of large immune components, such as antibodies and complement proteins, to the conserved inner regions of the LPS. This external shield allows the bacterium to survive within the host, making the O-Antigen a factor in bacterial virulence.
How LPS Triggers the Immune System
The biological consequence of LPS structure becomes apparent when Gram-negative bacteria die and lyse, releasing the endotoxin into the host’s bloodstream or tissues. The immune system is sensitized to detect this foreign structure, specifically recognizing the Lipid A component. This recognition is mediated by specialized immune cells, primarily macrophages and monocytes.
The process begins with Lipid A binding to a circulating protein, which facilitates the transfer of the endotoxin to receptors on the immune cell surface. The main sensor is Toll-like receptor 4 (TLR4), part of the innate immune system’s pattern recognition machinery. Binding Lipid A to the TLR4 complex initiates an intracellular signaling cascade.
Activation of the TLR4 pathway triggers the production and release of pro-inflammatory signaling molecules, such as tumor necrosis factor-alpha (TNF-$\alpha$) and various interleukins. While localized release helps clear a simple infection, a systemic release of large amounts of LPS during severe infection can lead to an uncontrolled inflammatory response. This widespread inflammation can cause fever, a drop in blood pressure, and tissue damage, resulting in septic shock.