Why Mice Succumb to Human Diseases

Evolution in the Lab: Researchers of the Helmholtz-Association reveal how Pathogens adapt to new Victims

The bacterium Listeria monocytogenes is able to infect humans causing diarrhea, meningitis, still birth or miscarriage. Mice, by contrast, are largely immune. This difference may be traced to the bacterial protein Internalin (or InlA), a molecular key that provides the bacterium with a route of access to cells lining the small intestine. In mice this mechanism is disabled, so that bacteria are unable to cause an infection. This represents a distinct disadvantage for medical research as new treatments cannot be tested using mice. Researchers at the Helmholtz-Centre for Infection Research in Braunschweig, Germany, now demonstrate how a minor modification in InlA enables the bacterium to infect mice.

In nature, bacteria change continually. “Most newly emerging infectious diseases, including the plague in the Middle Ages and the current bird flu, result from animal pathogens suddenly adapting to humans,” says Dr. Wolf-Dieter Schubert, group leader at the Helmholtz-Centre for Infection Research. “We refer to this as a change in host specificity. The adaptation of the influenza virus H5N1 from birds to humans has, in this context, not only been a major concern for the general public, but has also resulted in appreciable economic losses.” This is also true for HIV, the causative agent of AIDS, which was able to bridge the gap between apes and humans.

We have simulated this breaching of the host barrier in the lab – but in the opposite direction, namely from humans to animals” describes PhD-student Thomas Wollert. “This was possible because we understand the three-dimensional structure of InlA in atomic detail.

During listerial infections, InlA allows the bacteria adhere to the surface of the intestinal lining. This is possible because InlA recognizes its receptor E-cadherin located on the corresponding cells with high precision. E-cadherin is also present in the intestine of mice, but differs from its human counterpart in small but crucial sites.

“As a result, InlA recognizes human E-cadherin but not the variant found in mice ” says Thomas Wollert. “If we only replace two of 764 amino acid building blocks of InlA, it binds more tightly to human E-cadherin but, more significantly, it additionally recognizes the murine version.” Similar substitutions of such building blocks happens spontaneously in nature. “If we understand the principles governing the host specificity of pathogens,” declares Dr. Schubert, “we should  be able to predict in advance, which pathogens are particularly likely to adapt to humans”.


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