Overcoming Immune Tolerance Requires an Enzyme that Eliminates LPS

During the period of immune tolerance induced by the host's response to bacterial infection the individual is highly susceptible to further infection until immune system function is reset by elimination of residual lipopolysaccharide (LPS) endotoxin.

LPS is a major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS is an endotoxin, and induces a strong response from normal animal immune systems. LPS acts as the prototypical endotoxin, because it binds the CD14/TLR4/MD2 receptor complex, which promotes the secretion of proinflammatory cytokines in many cell types, but especially in macrophages.

Investigators at the University of Texas Southwestern Medical Center (Dallas, USA) examined the role of acyloxyacyl hydrolase (AOAH), an enzyme that removes nonhydroxylated fatty acids from the lipid A moiety of LPS, in the reestablishment of immune system function. To this end, they genetically engineered a line of mice to lack the gene for production of AOAH. The "knock-out" mice and a group of normal control animals were primed with either an injection of LPS or a mild infection with Gram-negative bacteria. Two weeks later, the animals were infected with a highly virulent form of Escherichia coli.

Results published in the September 11, 2008, online edition of the journal Cell Host & Microbe revealed that more than 90% of the "knock-out" mice were killed by the E. coli while nearly all the control animals survived. The animals lacking AOAH had failed to recover from the state of immune tolerance induced by LPS.

"We think this is the first evidence that killing the causative agent of a bacterial infection is not enough for an animal to recover fully,” said senior author Dr. Robert Munford, professor of internal medicine and microbiology, at the University of Texas Southwestern Medical Center. "You have got to get rid of this molecule that the host is responding to or else its immune system remains suppressed. We do not have any evidence that this finding is applicable to humans, who also make the enzyme, but it is possible. One theory is that there is variability among humans in the production of acyloxyacyl hydrolase. We do not know this yet, but if it is true, then the presence or absence of the enzyme might contribute to the length of immunosuppression after serious bacterial infections. It might even be reversible if we could provide the enzyme or figure out a way for people to make more of it.”

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University of Texas Southwestern Medical Center