Modifications in lipopolysaccharide that reduce interaction of bacterial pathogens with the innate immune system and cause resistance to antimicrobial peptides
Resumen: In Gram-negative bacteria, lipopolysaccharide (LPS or endotoxin) is the major component of the outer leaflet of the bacterial cell wall and one of the most potent immunostimulary molecules known. The basic structure of LPS is highly conserved among Gram-negative organisms and consists of a polysaccharide (O-chain) covalently linked to a membrane-bound glycolipid (lipid A) through a core oligosaccharide. The inner sections of LPS are highly anionic due to numerous phosphoryl and carboxyl groups present in its core and lipid A sections.
Even at exceedingly low concentrations, LPS is detected by innate immune system cells bearing the TLR-4/MD-2 receptor-coreceptor, and this recognition induces beneficial responses including moderate fever and local inflammation. However, release of high concentrations of endotoxin by pathogens into the bloodstream triggers acute systemic reactions that may lead to septic shock and eventually to multiorganic failure and death.
Antimicrobial peptides (AMPs) are produced by virtually all types of organisms, and often constitute the first line of defense against microbial pathogens. The highly positive charge of AMPs and their amphiphilic character allow them to bind to anionic residues of the bacterial surface (mainly LPS in Gram-negative bacteria) and to rapidly kill their
targets. In addition, AMPs can bind and sequester LPS in vivo, thus hampering recognition of this molecule by the immune system. In fact, treatment with AMPs has been shown to prevent sepsis and septic shock in animal models of endotoxemia.
The most important mechanism of resistance to AMPs in Gram-negative bacteria involves the expression of LPS variants with the ability to reduce interaction with AMPs. The LPS modifications include changes in electronegativity and/or hydrohobicity and can affect all the sections of the molecule.
Whereas some bacteria are intrinsically resistant to AMPs, others have sophisticated systems of AMP detection coupled to their LPS modification machinery. In this chapter, we will review examples of both types of strategies and will describe how some prominent human pathogens (Proteus spp, Yersinia spp. Brucella spp., Salmonella spp., Bordetella spp. and Escherichia coli) modify their LPS and how these alterations affect the bacterial resistance to AMPs. Interestingly, reduced ability to interact with AMPs correlate in some cases with changes in LPS recognition by cell receptors of the immune system. In addition, bacterial cells expressing these altered LPS display profound changes in virulence and endotoxicity. Examples of these correlations will be discussed in detail throughout the chapter.