Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant?

Much is known about both microbial virulence and host defense mechanisms, and yet how they interact to produce different clinical outcomes is poorly appreciated. Here I review evidence that the clinical manifestations of gram-negative bacterial diseases can be influenced by how and where animal hosts sense the major gram-negative bacterial “signal” molecule, the cell wall lipopolysaccharide (LPS). Clinicians know LPS best by the inaccurate name “endotoxin. ” In fact, animals sense and react to LPS molecules that are on the bacterial surface, or released from it, and the ensuing inflammatory reaction is usually protective rather than harmful. Whereas the polysaccharide component of LPS differs between strains, the lipid A moiety retains certain features in almost all gram-negative bacteria, and it is this semiconserved structure that animals can sense to detect the presence of many gram-negative bacteria in their tissues (Fig. ​(Fig.1). 1). Genes that encode the host sensory mechanism, a complex that includes both MD-2 (LPS binding) and Toll-like receptor 4 (TLR4; signal transduction), have been found in almost all studied vertebrate genomes (110). Intracellular signaling pathways downstream of TLR4 mediate both pro- and anti-inflammatory responses to infection. FIG. 1. Structure of E. coli lipid A. The diglucosamine lipid A backbone has phosphates at positions 1 and 4′ and two molecules of 3-hydroxymyristate attached directly to each glucosamine. The hydroxyl groups of the hydroxymyristates at positions 2′ . A prominent role for host-LPS interactions in the pathogenesis of gram-negative bacterial diseases is plausible because LPS is the gram-negative bacterial molecule that vertebrates seem to detect most sensitively. As was first shown by Darveau and colleagues, intact Escherichia coli cells do not stimulate human endothelial cells when their LPS lacks one of the six fatty acyl chains that are attached to lipid A (124). Others have extended this finding to different gram-negative bacteria and host cells, and there is now much evidence that recognizing lipid A (LPS) is the most sensitive and specific mechanism by which animals detect gram-negative bacteria (10, 28, 30, 68, 72). On the other hand, gram-negative bacteria can also be sensed by other host receptors, and important innate defenses (such as complement activation) are not activated by lipid A. Moreover, not all gram-negative bacteria make LPS that can be recognized by MD-2-TLR4. Many of the bacteria that can be sensed by MD-2-TLR4 are commensal or pathogenic aerobes that live on the mucosae of the upper respiratory or gastrointestinal (GI) tracts. In immunocompetent hosts, these bacteria usually elicit local inflammation without invading the bloodstream. One may thus hypothesize that the MD-2-TLR4 defense limits bacterial invasion to the submucosa, preventing systemic dissemination (91). In contrast, many gram-negative bacteria that cause systemic infections in humans produce LPS molecules that are poorly sensed by MD-2-TLR4, and so they escape recognition by this key defense mechanism. According to this schema, both the presence and the absence of TLR4-activating LPS can contribute to disease expression. The evidence reviewed below generally supports this notion, yet prominent exceptions highlight its weaknesses as a guiding framework and suggest areas for future research. A discussion of how animals recognize microbes is given as a background and rationale for the description of clinical associations that follows. Here “disease” is used to denote infections that in some way damage the host; “commensal” refers to bacteria that can infect for long periods without inducing disease (normal microbiome); and “pathogens” are microbes that cause or elicit damage (99).