Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock

Abstract

Bacterial sepsis and septic shock result from the overproduction of inflammatory mediators as a consequence of the interaction of the immune system with bacteria and bacterial wall constituents in the body. Bacterial cell wall constituents such as lipopolysaccharide, peptidoglycans, and lipoteichoic acid are particularly responsible for the deleterious effects of bacteria. These constituents interact in the body with a large number of proteins and receptors, and this interaction determines the eventual inflammatory effect of the compounds. Within the circulation bacterial constituents interact with proteins such as plasma lipoproteins and lipopolysaccharide binding protein. The interaction of the bacterial constituents with receptors on the surface of mononuclear cells is mainly responsible for the induction of proinflammatory mediators by the bacterial constituents. The role of individual receptors such as the toll-like receptors and CD14 in the induction of proinflammatory cytokines and adhesion molecules is discussed in detail. In addition, the roles of a number of other receptors that bind bacterial compounds such as scavenger receptors and their modulating role in inflammation are described. Finally, the therapies for the treatment of bacterial sepsis and septic shock are discussed in relation to the action of the aforementioned receptors and proteins.

FIG. 1.

Cell wall structure of bacteria. All types of bacteria contain a cell membrane surrounded by a PGN-containing layer. LTA and LAM are inserted into the cell membrane of gram-positive bacteria. LPS forms the outer layer of the outer membrane of gram-negative bacteria. The mycobacteria also contain a carbohydrate shell, but not all bacteria contain a capsule.

FIG. 2.

Structure of lipid A (443) (A) and whole LPS (B). The composition and length of several LPS serotypes are indicated.

FIG. 2.

Structure of lipid A (443) (A) and whole LPS (B). The composition and length of several LPS serotypes are indicated.

FIG. 3.

Structure of LTA from S. aureus (131). Ala, alanine.

FIG. 4.

Binding of bacterial ligands to CD14 and sCD14. The involvement of LBP, (s)CD14, and TLR2 and TLR4 in the activation of CD14-expressing cells (e.g., macrophages) and of cells that do not express CD14 (e.g., endothelial cells) is shown. LPS (left) and PGN (right) represent TLR4- and TLR2-specific ligands, respectively.

FIG. 5.

TLR signaling pathways. The shared signaling pathway for TLR2 and TLR4 is depicted. IRAK, IL-1R-associated kinase; TRAF6, tumor necrosis factor receptor-associated factor 6; TAK1, transforming growth factor β-activated kinase; TAB1, TAK1-binding protein; NIK, NF-κB-inducing kinase; MKK, mitogen-activated protein kinase kinase; JNK, c-Jun N-terminal kinase; IKK, IκB kinase; AP-1, activator protein 1.

FIG. 6.

Structure of the SR-As.

FIG. 7.

LPS and LTA transfer to lipoproteins. Black arrows indicate established pathways. In contrast to LPS (left), LTA may also associate with lipoproteins in the absence of LBP (extra arrow in right panel).