The systems biology of infection in animal models bears fruit

The host response to pathogenic bacteria defies simple, general descriptions. The complicated nature of these interactions is a natural consequence of the complexity of the participants: bacteria, which are free-living organisms with genomes encoding thousands of genes, and mammals and plants, which are multicellular organisms with elaborate genomes orders of magnitude larger. The diversity of hosts and bacterial pathogens further complicates a straightforward, comprehensive portrayal of infectious diseases. Despite this complexity, the relative conservation of innate immune responses has provided a basis for our understanding of bacterial diseases that transcends the differences among hosts and infectious agents. These recently identified innate immune response pathways, which regulate the adaptive immune response to infections through the production of biologically active cytokines, offer a valuable framework by which infectious diseases can be classified and defined (1). In the article by Handley et al. in a recent issue of PNAS (2), the combined use of two powerful experimental techniques yielded entirely unexpected information regarding the innate immune response to bacteria by using a well studied host–pathogen model: Yersinia entercolitica infection of susceptible, inbred mice.

The development of mammalian cell culture infection models has improved the throughput of bacterial pathogenesis research and greatly advanced our knowledge of the mechanisms by which bacterial pathogens alter host cells (3). These methods, coupled with advances in genomic and proteomic technologies, provide a powerful means to define responses essential for host defense. However, these model systems do not offer the opportunity to study infections within the context of intact tissues or animals. Animal models can be used to define the interactions of pathogens with complex tissues, such as mucosal surfaces. However, these models also are limited in their reflection of natural disease. For example, different animal models involving inbred mice (frequently with unique innate immune responses) can yield apparently …

^‡To whom correspondence should be addressed. E-mail: millersi{at}u.washington.edu