Modeling Infectious Disease in Mice: Co-Adaptation and the Role of Host-Specific IFNγ Responses

The advantages of the mouse as a model organism in biomedical research are many. The molecular and genetic toolbox developed for the mouse over the last 100 years enables researchers to manipulate and study gene function in vivo almost at will. Time and time again, scientific findings obtained through the use of mouse models have proven to be relevant to human health. The field of immunology in particular has profited tremendously from the powers of the mouse model and much of our knowledge of the workings of the immune system is derived from studies performed in mice. Yet all that glisters is not gold. Researchers have used the mouse extensively as a model organism to study the pathogenesis of human infections and found that it imperfectly recapitulates many aspects of infectious disease as seen in patients. In fact, mice generally appear to be highly resistant to infections with human-specific pathogens like HIV, Plasmodium falciparum, and Shigella flexneri, especially if the pathogen is administered through the natural route of infection. Of course, the inherent resistance of mice to highly adapted human pathogens should not be a surprise: because pathogens co-evolve with and adapt to their preferred host, their successful specialization often renders them highly dependent on their host species [1]. Such host tropism or host restriction limits the usefulness of the mouse as a model for infectious disease research. One approach to overcome the limitations of the mouse model could be to genetically engineer mice that closely resemble humans in all those aspects relevant for host–pathogen interactions. To assess how realistic this ambitious goal may be, we must first understand the underlying molecular causes for host restriction.