Chapter 2: Kill the bacteria...and also their messengers?

Abstract

We consider here a previously neglected aspect of recovery from infectious diseases: how animals dispose of the dead microbes in their tissues. For one of the most important disease-causing microorganisms, Gram-negative bacteria, there is now evidence that the host catabolism of a key microbial molecule is essential for full recovery. As might be expected, it is the same bacterial molecule that animals sense to detect the presence of Gram-negative bacteria in their tissues, the cell wall lipopolysaccharide (LPS). Here, we discuss current knowledge about LPS sensing with emphasis on the host enzyme that inactivates this microbial "messenger" molecule. We also consider the possibility that the rate at which stimulatory microbial molecules undergo inactivation may influence the duration and severity of diseases caused by other infectious agents.

FIGURE 2.1

The structure of Escherichia coli lipid A. Arrows indicate the acyloxyacyl-linkages. The secondary acyl chains are shown as dashed lines.

FIGURE 2.2

AOAH structure. The precursor (top) undergoes proteolytic processing to yield the mature protein (bottom). SAPLIP, sphingolipid activator protein-like peptide.

FIGURE 2.3

AOAH (left), with its covalently linked saposin-like subunit (SAPLIP), acts on the bacterial glycolipid, LPS, whereas glucosylceramidase (right), requires saposin C to cleave its eukaryotic glycolipid substrate, glucosylceramide.

FIGURE 2.4

(A) Aoah^+/+ and Aoah^−/− C3H/HeN mice had similar survival time-courses following intraperitoneal challenge with Neisseria meningitidis (5 × 10⁷ colony-forming units), yet (B) the surviving Aoah^+/+ mice recovered more rapidly than did the Aoah^−/− mice. Recovery was measured using a clinical scoring system that included piloerection, diarrhea, ocular exudate, immobility, and body weight.

FIGURE 2.5

(A) Antibody responses of Aoah^+/+(closed boxes) and Aoah^−/− (open circles) mice to a single subcutaneous dose of 10⁷ cfu live Neisseria meningitidis. (B) Antibody responses to a single injection of UT12 agonistic antibody to MD-2–TLR4. Note that the responses of Aoah^+/+ and Aoah^−/− mice were different only when LPS was used to activate MD-2–TLR4. N =3–5 mice/group. The data in (A) were published in Lu et al. (2005).