The spread of antimicrobial resistance is quickly outstripping the development of novel antibiotics, creating a looming danger for human health and well-being. One means for avoiding this health crisis is the identification of mechanisms to stimulate the innate immune system of the host instead, enabling increased microbial clearance. In addition, host stimulation is likely to prove a more difficult target for the adaptive genetic processes of microbes, as it unbalances the host-pathogen interaction, rather than simply killing the pathogen or preventing its replication. For this grant, I will utilize a novel C. elegans liqui infection assay that I have developed and characterized. C. elegans possesses evolutionarily conserved innate immune pathways similar to those of humans.
In Specific Aim 1, the mechanisms used by small molecules with immunostimulatory properties identified in my earlier efforts will be characterized. I will also determine whether this activity is conserved by testing or activation and polarization of murine macrophages. In this fashion, insights into mechanisms of immune activation in vertebrate model organisms will be gained, potentially identifying novel targets for human therapeutics.
For Specific Aim 2, I will investigate a mechanism of immune stimulation induced by rearing worms on a specific bacterial food source. The stimulatory mechanisms uncovered may yield new insights into intestinal infections, autoimmune disorders, and intestinal inflammatory conditions. Portions of each aim will be undertaken while I complete my mentored postdoctoral fellowship, but both will be completed once I have an independent position. My current environment, at both the institutional and the laboratory levels, is outstanding. Dr. Fred Ausubel, one of my mentors, pioneered the study of C. elegans innate immunity. Dr. Ruvkun is a leader in the field of stress responses in C. elegans. I've had the opportunity to be co-mentored by both of these exemplary scientists, maximizing my training. In addition, the facilities, equipment, and scientific environment at Massachusetts General Hospital and Harvard Medical School, where I am jointly appointed, are amongst the best in the world. I am interested in developing increased understanding about the integrated the responses to abiotic (e.g., hyperthermia, hypoxia, oxidative stress) and biological stresses (including infection, inflammation, and cancer). Toward that end, my career has focused on assembling the skills necessary to probe these pathways. My immediate career plans include publication of ongoing analysis regarding the host aspect of the liquid killing assay that I have developed. This will more solidly ground the findings that will be acquired during this grant. The next important step in that progression involves a transition to an independent position and acquiring preliminary data for an R01 grant application, which will be greatly facilitated by the acquisition of this grant.
The expanding threat of antimicrobial resistance is rapidly outstripping the development of novel antibiotics, leading to a burgeoning menace of untreatable bacterial infections. We use a small worm to identify mechanisms to stimulate the immune system. During this project, I will characterize chemical and microbiological immunostimulatory mechanisms in detail and test whether they are relevant in mammals.
