Our laboratory uses genetic and functional genomic methodologies to study the genetic basis of innate immunity using C. elegans and mammalian systems. Recent studies from our laboratory highlight the importance of the nervous system in the regulation of innate immune responses. Using a genetic approach we were able to demonstrate that specific neurons can regulate innate immunity. We are studying a number of signaling molecules that can be used by the nervous and immune system to communicate to each other. We infect the Caenorhabditis elegans model host with different human bacterial and fungal pathogens to understand host-pathogen interactions. We also use mammalian systems to study innate immunity and microbial pathogenesis.
Another line of investigation we are pursuing concerns the identification and characterization of receptors potentially involved in pathogen recognition and activation of immune responses. We have demonstrated that the only Toll-like receptor in C. elegans, TOL-1 is required to prevent the invasion of pharyngeal cells by the human pathogen Salmonella enterica. The study of candidate downstream components of the TOL-1 pathway indicate that TRF-1, but not IKB-1, may be required for the effects of TOL-1 in immunity and that there may be other downstream components that regulate TOL-1-mediated immunity in a redundant manner. We are also studying the immune function of the scavenger receptor CED-1 and a system of proteins involved in the unfolding protein response (UPR) that are required to prevent bacterial invasion of host cells.
In addition to pathogen recognition and activation of microbial killing pathways, another important aspect of innate immune response is fever. Fever is an ancient immune mechanism used by metazoans in response to microbial infections. In mammals, several studies have been conducted to understand the mechanism of fever elicitation and to develop antipyretic therapeutics. However, the mechanism by which increased temperature exerts its beneficial role remains unclear. We use C. elegans to study the mechanism by which increased temperatures activate the innate immune system.
We are also characterizing different C. elegans mutants that are either more resistant or more susceptible to
pathogens. Since several components of innate immunity are conserved among different organisms throughout evolution, understanding the basis of the immune response in C. elegans should provide new insight into some aspects of immunity in mammals.
Finally, we study the mechanisms by which bacterial virulence factors required for virulence in both nematodes and mammals target conserved innate immune pathways. We have demonstrated that S. enterica genes related to the type three secretion system (TTSS) are expressed in the C. elegans intestine and required for full virulence. We also showed that the S. enterica TTSS-exported effector protein SptP inhibits a conserved P38 MAPK signaling pathway. In addition to S. enterica, we also perform studies using a variety of human pathogens including Yersinia pestis, Pseudomonas aeruginosa, Staphylococcus aureus, and Cryptococcus neoformans.
Education and Training
- Research Fellow, Genetics, Harvard University, 1999 - 2002
- Research Fellow, Cell Biology And Physiology, Washington University, 1998 - 1999
- Ph.D., Universidad Nacional De Cuyo (Argentina), 2000
- M.A., Universidad Nacional De Cuyo (Argentina), 1995
- Pharm.D., Universidad Juan Agustin Maza (Argentina), 1994
Selected Grants and Awards
- C. elegans to study organismal control of recovery from bacterial infections
- Genetics Training Grant
- Duke Research Training Program for Pediatricians
- Center for Molecular & Cellular Studies of Ped Disease
- Genetic analysis of innate immunity using C. elegans
- Training Program in Developmental and Stem Cell Biology
- Institutional Training Grant in Pediatric Infectious Disease
- Organization and Function of Cellular Structure
- IsoCyte Laser Scanning Plate Cytometer for High-throughput, High-content Assays
- COPAS BIOSORT Worm Sorter
- Investigating post-translational regulation of innate immunity in C. elegans
- Role of Cell Death Pathway in C. elegans Innate Immunity
- Regulation of Innate Immunity by Virulence Factors
- Boosting innate immunity against Yersinia pestis
- Role of Lectin Genes in C. elegans Innate Immunity
- Role of Tyrosine Kinases & Adaptor Proteins in Migration