Lipopolysaccharide Heterogeneity In Bacterial Pathogenesis

There is, of course, a prototypical or model type of endotoxin structure represented by that occurring in EC and Salmonella and other Enterobacteriaceae. However, variations are being found in the prototypical structure, which was once thought to be fairly static, at least within the Lipid A portion. Variations are being found not only in different organisms but also within species that have adapted different LPS presentations as a means of aiding host invasion or to remain undetected while residing inside the host. The differences in O-chain, core, and Lipid A acyl chain structures are referred to as the "heterogeneity" or subsets of the (proto) typical structure (29), which is the most studied and among the most toxic of structures (as described in Chapter 4).

Enterobacterial endotoxins were initially studied and modeled as host-reactive and this served to encourage researchers to lump together the mode of action of all LPS moieties—until the discovery of the various "exceptions to the rule" which now appear to be as common as the "rule." Both intra and interspecies polymorphisms in LPS TLR have also been discovered. This brings with it the realization that the host reaction is far more complex, even for the prototypical pathogen-associated microbial patterns (PAMP) LPS, than previously believed. Perhaps of more practical significance is the difference that can arise in the Limulus amebocyte lysate (LAL) activity of various organisms for some of these (heterogeneity) reasons. EC, for example, is a hundred-fold more LAL reac-tivej than Shigella flexneri and greater than two-fold less active than Pseudomonas testosterone (30). Even different strains of organism used as the standard, EC, have shown exaggerated swings in endotoxicity via a variety of measures including LAL testing, with a range of six hundred-fold using a variety of serotypes (31).

jThe great utility of the LAL test here can be seen in that the biosensor, factor C, in Limulus is not a cell-bound TLR but rather a free hemolymph protease cascade initiator.

It is also interesting to note that although the presence or absence of LPS is an absolute (as are the presence of other features such as sporulation and flagella formation), it has become clear that this simple trait is not so simple when viewed from the genetic level. Consider that the genome of Archaea, Thermoanero-bacter tengcongensis (isolated from a freshwater hot spring in China), does not contain LPS but contains some of the enzymes used in the biosynthesis of LPS (32):

T. tengcongensis, as a gram-negative rod by staining, shares many genes that are characteristic of gram-positive bacteria but lacks some characteristics of gram-negative bacteria The T. tengcongensis, though having a few coding sequences (CDS) for LPS biosynthesis (TTE0652 and TTE0199), does not possess three of the key genes: the one related to LPS biosynthesis (LPS: glycosyltransferase, COG1442), and the two related to LPS transport (i.e., a periplasmic protein involved in polysaccharide export, COG1596) and an ATPase component of ABC-type polysacharide/polyol phosphate transport system COG1134. At least one of these three CDS is present in most of the gramnegative prokaryotes, such as Pseudomonas aeruginosa, V. choleraserotype, Neisseria meningitidis, X. fastidiosa, and EC ... none of the four CDS involved in Lipid A synthesis are found in the T. tengcongensis genome ...

The following subsections describe the efforts of some pathogens to inhabit the host by means of changing their LPS and other surface structure presentations, typically either to hide or disguise their presence upon gaining entry to the host or to alternatively ramp up their ability to effect a change in the host system status quo to favor their proliferation. Table 1 gives an overview of some LPS modification mechanisms and Table 2 gives the result or effect(s) upon the host.

Two interesting mechanisms that serve to demonstrate the utility of LPS heterogeneity occurring in the oligosaccharide-antigen (O-antigen) region are host mimicry and phase variation. The next section focuses on the LPS of a pathogen, Nesseria meningitides, that employs both methods and is followed by two additional sections that describe various other means of LPS heterogeneity in host occupation: Yersinia pestis, and Porphyromonas gingivalis. Nesseria meningitides contains truncated O-antigens referred to as lipooligosaccharides (LOS). They are able to add sialic acid residues to the short chains to create structures mimicking host cell constituents (33).

TABLE 1 Lipopolysaccharide Heterogeneity in Pathogens

Heterogeneity mechanism

Sub-mechanism(s)

Example organism(s)

Comments

O-antigen structural variation

Antigenicity (i.e., typical adaptive host response) Host mimicry

Phase variation

Lipid A acyl group variation/phase variation

Escape of TLR4

pathway activation Production of agonistic and antagonistic LPS

All gram-negative orgs.

Nesseria meningitides,

H. pylori Nesseria meningitides,

H. pylori Bordetella, Yersinia pestis

Helicobacter Pylori

Porphyromonas gingivalis

~1,000 O-antigenic variants in Salmonella and ~200 in E. coli See section "O-antigenic

Variation-Phase variation..." See section "O-antigenic

Variation-Phase variation..." Arthropod-borne pathogens, many of which cause fevers via gram-negative pathogens. See Chapter 5 Activates TLR2 which is not typically a LPS toll pathway Atypically activates TLR2 and TLR4

Abbreviations: LPS, lipopolysaccharide; TLR, Toll-like receptors.

TABLE 2 Summary of the Response of Each TLR4-MD-Z Combination to Various Ligands. Phenotype Relative to Escherichia coli Lipopolysaccharidea
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