Infectious diseases are major causes of death, disability, social and economic disruption for millions of people worldwide. They also impose major limitations on agricultural productivity. The Molecular Pathogenesis group conducts innovative basic research in the area of cellular and molecular mechanisms of infectious diseases. We seek to understand the biology of microbial signaling systems, exploitation of host cell functions by pathogenic organisms, and mechanisms of protective host immune responses to infections. The model microorganisms used in our research are important pathogenic agents of humans, animals and plants. These include Legionella, Salmonella, E. coli, Agrobacterium, herpesviruses, togaviruses and flaviviruses. Our research groups maintain well-equipped laboratories and have access to highly sophisticated instruments in the adjacent Bindley Bioscience Center, facilitating the use of state-of-the-art molecular, biochemical, cellular, and structural approaches in our studies.
The Molecular Pathogenesis group fosters high quality scholarship and provides interdisciplinary undergraduate, predoctoral and postdoctoral trainings in cellular and molecular mechanisms of infectious diseases. In addition to the weekly departmental seminar series, the group organizes regular research presentations and journal clubs, and members are encouraged to attend national and international scientific meetings. Our research is supported by grants from the NIH, the NSF, and other extramural and intramural funding agencies.
Our research investigates how a soil bacterium, Agrobacterium tumefaciens, genetically engineers plants. Agrobacterium transfers a piece of bacterial DNA, the T-(transferred) DNA, to wounded plant cells where it makes its way through the cytoplasm to the nucleus. Once in the nucleus, T-DNA integrates into the host genome and expresses genes. Under normal circumstances, these genes cause the tumorous disease Crown Gall on plants. However, scientists have learned to manipulate T-DNA, replacing disease genes with genes of benefit to the plant. Many genetically engineered crop plants with desirable traits (disease resistance, herbicide tolerance, and enhanced nutritional value) were generated using Agrobacterium. Our laboratory investigates the role of plant genes and proteins in this natural genetic engineering process. We have identified plant genes involved in bacterial attachment to plant cells, T-DNA and Virulence protein transfer to and cytoplasmic trafficking within plants, T-DNA nuclear targeting, and T-DNA integration. Recently, we have been able to manipulate some of these plant genes to improve Agrobacterium transformation efficiency. We are currently working with agricultural biotechnology companies to improve the genetic engineering of crops.
My laboratory is interested in the replication, assembly and structure of RNA viruses with an emphasis on their interactions with the host. Our molecular studies utilize cutting edge tools in functional genomics, high throughput systems technologies, cell biology, and structural biology. Our focus in recent years has been on model systems in the alphavirus and flavivirus groups, and include viruses such as Sindbis, Chikungunya, dengue, West Nile, and hepatitis C viruses. Most of these human viruses are transmitted by insect vectors and therefore alternate between widely diverse hosts. Directly related to our basic studies is application-based research that seeks to identify new therapeutics for disease intervention.
Our laboratory is interested in understanding the cellular and molecular mechanisms that allow microbial pathogens to survive and multiply within the hostile host cells. We use Legionella pneumophila, the causative agent of Legionnaires disease as a model organism. This bacterium is a facultative intracellular pathogen capable of growing in a vacuole within macrophages as well as fresh water amoebae. After uptake, the Legionella-containing vacuole (LCV) in its early phase evades fusion with the lysosomal network and later is transformed into a compartment with characteristics of rough endoplasmic reticulum. Biogenesis of this replicative vacuole requires the Dot/Icm Type IV secretion system that injects hundreds of effector proteins into target host cells. Our current focus is to analyze biochemical and cell biological activities conferred by these proteins and their roles in promoting the unique trafficking of the Legionella-containing vacuole in phagocytic cells. In particular, we are interested in identification of host proteins whose activities are modulated by substrates of the Dot/Icm system and how such modulation contributes to successful intracellular bacterial growth. The long term goal of these studies is to elucidate the molecular mechanisms underlying how this bacterium subverts host signal transduction pathways to establish a successful infection, such information will be invaluable in combating diseases caused by Legionella and other vacuolar pathogens.
(Biochemistry, Signal Transduction, and Microbiology) Investigation of Fic domain containing proteins in Cellular Signaling.
My research focuses on the cell biology of infectious diseases, in particular human intestinal diseases caused by pathogenic Salmonella and E. coli. These pathogens cause intestinal diarrhea and may lead to more serious systematic infections in humans. Both pathogenic Salmonella and E. coli utilize the type III protein secretion/translocation system (TTSS) to inject bacterial "effector proteins" into host cells to exploit host cell functions to survive in the hostile environment and cause inflammatory responses. We aim to understand the molecular and cellular mechanism of how these effectors function to enable the pathogens to circumvent our host immune system to cause diseases. We currently have projects studying the role(s) of actin dynamics in Salmonella and E. coli infections and how bacterial effectors exploit the host ubiquitination pathways to induce inflammatory responses.