The immune system is the body's line of defense against disease-causing bacteria, viruses and fungi. In order to carry out its function the immune system must be able to distinguish self from non-self. If the immune system fails to detect foreign invading pathogens, the body succumbs to infection and possible death. On the other hand, if the system mounts an attack against its own tissues, autoimmunity can develop.
It has been recently appreciated that the crucial ability of the immune system to quickly detect foreign invading pathogens is a function of an evolutionarily ancient arm of the system, termed the innate system. Cells of the innate system have evolved to distinguish pathogens from self by recognizing highly conserved pathogen-associated molecular patterns (PAMPs) through a similarly-conserved array of surface-associated pattern-recognition receptors (PRRs). PRRs used by mammalian immune systems have been identified in organisms as diverse as horseshoe crabs, tomatoes, worms and fruitflies. In fact, some of the ground-breaking work in identifying the PRRs by which innate immune systems recognize invading pathogens was completed in fruitflies.
The slime mold Dictyostelium discoideum is a unique model organism that exists for part of its lifecycle as unicellular amoebae but is induced to form a multicellular sporulating body upon starvation. The amoeboid cells phagocytose bacteria for nutrient uptake, and this process is utilized in higher organisms by innate immune cells to eliminate invading bacteria. Due to the ease with which they can be cultured and genetically manipulated, Dictyostelium amoebae have long been used to study the process of phagocytosis. It has not been appreciated, however, whether Dictyostelium detect bacteria using the same types of PRRs as do innate immune cells.
The research in our laboratory is aimed at studying Dictyostelium responses to known PAMPs found in bacteria, fungi and viruses. Our preliminary studies have revealed that Dictyostelium amoebae can indeed respond to known PAMPs, suggesting that elements of the pattern-recognition machinery used by innate immune systems in higher organisms are conserved. We are taking advantage of the manipulability of the Dictyostelium genome to identify and study particular gene products that may be involved in the Dictyostelium response to PAMPs. Characterization of such proteins in Dictyostelium may allow for identification of novel players conserved in the innate immune systems of mammals.
Although the immune system has developed to recognize and eliminate foreign organisms, various pathogens have evolved strategies to evade immune responses. Some pathogens such asMycobacterium tuberculae have evolved strategies to evade mammalian immune surveillance by acquiring the ability to survive within phagosomes of innate immune cells. Recent studies have shown that microbial pathogens also can infect and survive within phagosomes of Dictyostelium. We are working to develop a model system using Dictyostelium and Mycobacterium bovis BCG (a weakened Mycobacterium strain that is safely administered as part of a vaccine for tuberculosis in much of the developing world). We hope that such a system will allow us to translate our findings related to pattern recognition in Dictyostelium to host-pathogen interactions in human diseases such as tuberculosis.
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