last updated April 2013
Preventing bacterial sabotage
By revealing how different bacterial toxins bind immune proteins, researchers hope to prevent the deadly effects of infection
During bacterial infection, some of the worst damage can be wrought by the body’s own defenses. Certain bacteria display cell-surface molecules called lipopolysaccharides (LPS), which interact with immune cell receptors and can potentially trigger a catastrophic overreaction that leads to septic shock and death.
Different LPS subtypes exhibit different levels of toxicity, due primarily to variability in a segment called ‘lipid A’. University of Tokyo researcher Toshiyuki Shimizu and colleagues in Japan have clarified the effects of different lipid A-receptor interactions1. Since lipid A binds two immune proteins, TLR-4 and MD-2, the researchers performed structural analyses revealing how the highly toxic Re-LPS and less toxic lipid IVa act differently on the mouse and human versions of these two proteins.
A key difference between lipid A domains is the length and number of acyl chain chemical groups they possess: Re-LPS has six, while lipid IVa has four. Nevertheless, both molecules interacted similarly with mouse TLR-4/MD-2 to generate an active signaling complex. In the human complex, however, lipid IVa binds in a manner that essentially inactivates TLR-4/MD-2. Shimizu and colleagues subsequently identified structural differences in the human complex that may contribute to this altered binding, obtaining insights that could guide development of drugs that mitigate the toxic effects of LPS.