The goals of our research programs are to use genetic, molecular and genomics approaches to address fundamental and outstanding questions in host-pathogen interactions. Our laboratory’s efforts focus on the identification and characterization of (1) the virulence factors employed by pathogens to overcome host defenses, (2) the signaling pathways that are triggered, and the defense arsenal that is deployed, by the host in response to pathogens, and (3) the molecular mechanisms underlying the interaction between host- and pathogen-derived factors. To address these questions, we developed a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model, in which both the bacterial pathogen and the nematode host are amenable to genetic manipulation. We have extended this system to include other opportunistic human pathogens and invertebrate hosts.
First, to identify novel virulence factors, we screened for P. aeruginosa mutants that are defective in killing C. elegans. In humans, P. aeruginosa causes a broad spectrum of opportunistic infections in immunocompromised and cystic fibrosis patients. A majority of the novel P. aeruginosa virulence factors identified in the nematode host is also essential for mammalian pathogenesis. We are performing detailed characterizations of these genes. Second, we have isolated new C. elegans mutants that are either more sensitive or resistant to P. aeruginosa-mediated killing and determined that at least two evolutionarily conserved pathways are involved in C. elegans defense response. We are currently analyzing these genes and pathways to determine their precise role in C. elegans defense. Third, because the entire genome sequence of both the host and pathogen are available, we will be using the microarray technology to study genome-wide gene expression of both organisms as they interact.
Recently, it has been shown that the innate immune responses of evolutionarily divergent hosts, such as plants, insects and mammals are strikingly similar. Furthermore, the offensive factors employed by pathogens of these hosts have also been strongly conserved at the molecular level. Thus, the P. aeruginosa-C. elegans model has great potential to provide general insights into the molecular interactions between pathogens and hosts, including humans.