Worms and Flies as Genetically Tractable Animal Models To Study Host-Pathogen Interactions

Flies and worms have been chosen as model genetic organisms based on a number of traits that strike an excellent compromise between complexity and genetic tractability. Although an antibacterial defense system in flies was reported in the early 1970s (11), Drosophila melanogaster actually emerged as a model animal to study innate immunity 20 years later, when the first parallels between mammalian and Drosophila innate immunity were discovered after a NF-κB/Rel protein was found to translocate to the nucleus in response to microbial infection (39, 53, 76). In addition, in seminal studies Lemaitre et al. demonstrated that Toll and imd genes control the expression of antimicrobial defense in D. melanogaster and showed that mutations in the Toll signaling pathway dramatically reduce survival after fungal infection (52, 54). Caenorhabditis elegans emerged a few years later when Tan et al. reported in 1999 that the nematode can be used to model Pseudomonas aeruginosa pathogenesis in mammals (82). Since then, these organisms have been extensively used to study host-pathogen interactions (reviewed in references 1, 5, 14, 35, 50, 69, and 78). As in vertebrates, physical barriers and antimicrobial substances protect D. melanogaster and C. elegans from microbial attacks, but successful microorganisms are capable of overcoming the first line of defense by causing infections that in many cases result in the death of the infected animal. Although the interactions between D. melanogaster and C. elegans and a wide variety of microorganisms are somehow artificial, since these animals have not been described to be the natural hosts, they appear to have evolved mechanisms to respond to different microorganisms with some degree of specificity (18, 21, 22, 38, 40, 55, 59). In the case of D. melanogaster, growing evidence shows that certain microorganisms are capable of penetrating the exoskeleton or the intestinal epithelium to cause an infection following the so-called “physiological” or “natural” route of infection (85). The physiological infection consists of either (i) feeding D. melanogaster larvae or adult flies with the microorganism of interest distributed in the food or (ii) spraying fungal spores or microorganisms directly onto the fly exoskeleton. Various microorganisms, however, are unable to break the first line of defense and need to be inoculated. This is accomplished by (i) pricking the dorsal part of the fly thorax (or abdomen) body cavity of the insect with a sharp needle that has been dipped into a microbial suspension or (ii) microinjecting a precise dose of microbes directly into the body cavity. The disadvantages of these methods are that the mechanical manipulation itself appears to affect the host defense response to some extent and that there seems to be significant differences in the Drosophila defense response depending on the route of inoculation (7). In contrast, all the C. elegans pathogens described so far seem to use a relatively more physiological route of infection. Typically, C. elegans animals are propagated in the laboratory on petri dishes containing a lawn of a slow-growing strain of Escherichia coli OP50. The nematodes, which feed almost constantly during their adult life cycle, use muscle contractions to pump food into the pharynx where the pharyngeal grinder uses specialized cuticular structures to effectively disrupt most bacteria. Thus, essentially no intact E. coli cells can be found in the intestinal lumen. However, when C. elegans is fed certain human pathogens, the nematodes die and, in many cases, intact microorganisms can be found within the intestine (4, 28, 41, 48, 71, 82). A specific C. elegans pathogen, Microbacterium nematophilum, has also been isolated. These bacteria adhere to the anal region of the nematodes and induce localized swelling of the underlying hypodermal tissue. Although the C. elegans-M. nematophilum interaction is not lethal to the worm, it has been suggested to be pathogenic due to the morphological changes induced by M. nematophilum and lack of obvious benefits for the host (34). Studies on the D. melanogaster and C. elegans genomes have yielded new insights into the mechanisms of a variety of human diseases including Alzheimer's disease, stroke, cancer, retinitis pigmentosa, diabetes, and kidney diseases (33, 77). Here, we will discuss seminal genetic and functional genomic studies performed with D. melanogaster and C. elegans that have served to identify and characterize a variety of conserved innate immunity-related genes and virulence factors.