BioWorld International Correspondent
LONDON - A strain of mice that can resist bacterial infections could hold valuable clues to treating the septic shock that often follows overwhelming bacterial infection.
Tina Mahieu, a Ph.D. student working in the laboratory of Claude Libert at the department for molecular biomedical research at Flanders Interuniversity Institute for Biotechnology and Ghent University in Belgium, told BioWorld International: "We have found a mouse strain that produces less of an inflammatory cytokine when challenged with a bacterial cell wall component. Consequently, although they retain the ability to deal with bacterial infection, they do not suffer the harmful effects of excessive inflammation."
She described the phenotypes that she and her colleagues have identified as "very relevant in the search for new therapeutic interventions for sepsis."
The team discovered that the mice they studied produce only low levels of the cytokine called interferon-beta. Mahieu said: "We now want to find out which mechanism is responsible for these low levels of interferon-beta - for example, we will investigate if there is a defect in the pathway leading to production of interferon-beta."
Libert and Mahieu, together with collaborators from the U.S. and Germany, published their findings in a paper in the Feb. 1, 2006, issue of Proceedings of the National Academy of Sciences. Its title: "The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-b production."
Writing in the "Discussion" section, the authors described the strain of mice as having "the characteristics of a perfect therapy for sepsis." The mice, they wrote, are unresponsive to the toxic effects of a specific bacterial cell wall component, yet preserve their ability to recognize and destroy pathogens.
The authors concluded: "Probably the considerable reduction in interferon-beta in [this strain of] mice enables them to resist endotoxic shock, but the small amount that is still produced (about 10 percent of normal) is sufficient to stimulate innate and adaptive immunity. Therefore, detailed identification of the defect that leads to the down-regulation of [the interferon-beta pathway] could lead to a major breakthrough in sepsis research."
Libert and his team were studying the effects of a bacterial cell wall component called LPS on different strains of mice. LPS binds to a receptor on mammalian cells called TLR4, thus triggering a long series of reactions leading to elimination of the bacteria from the body, and inflammation.
The group already knew that there were a few strains of mice that were resistant to LPS. When wild-type mice are injected with a relatively low dose of LPS, they die, but the resistant animals are better able to withstand an injection of LPS. The in-bred strain known as SPRET/Ei survived particularly well. All of the animals tested survived a very high dose of LPS.
Studies showed, however, that while the other LPS-resistant strains succumbed easily to bacterial infections, the SPRET/Ei strain did not. Mahieu said: "The SPRET/Ei mice resist these infections. About 80 percent of them were still alive after eight days. With other strains, only about 40 percent survived, and in the case of one of the other known LPS-resistant strains, 100 percent died two days after infection."
Some existing LPS-resistant strains are known to have mutations in their TLR4 receptors. The Ghent team was unable to attribute the observed resistance of SPRET/Ei mice to an alteration in the TLR4 receptor, but other experiments they carried out demonstrated that the macrophages of SPRET/Ei mice produced only low levels of interferon-beta. When the researchers gave the animals interferon-beta, the animals were once again sensitive to LPS.
Mahieu said: "We conclude from this study that interferon-beta is an important molecule in this LPS-resistant phenotype."
A therapeutic application for the work is still a long way off. But Mahieu predicted that the mice "have strong anti-inflammatory genes. If we can find out what molecules are encoded by these genes, they may be of therapeutic value - we may be able to use them in the treatment of septic shock."
There already are some clues. It is known that when interferon-beta is produced, it binds to its receptor on the cell surface, and the binding, in turn, causes further production of interferon-beta.
"So there is a positive-feedback loop here," Mahieu said. "We have some data showing that levels of the interferon-beta receptor is lower in SPRET/Ei mice after stimulation with LPS, possibly contributing to the inefficient production of interferon-beta."
The team also is planning to investigate how the SPRET/Ei mice respond to infections with a range of different bacteria.