University of Virginia Health System

My research program is focused on molecular mechanisms of microbial pathogenesis and we use as model systems the infection of HeLa cells by Legionella pneumophila (the agent of Legionnaires' disease) and the infection of mice with Helicobacter pylori (the ulcer causing bacterium). Legionella pneumophila is an intracellular parasite of fresh water amoeba that when transmitted by aerosol to humans often causes severe pneumonia. Legionnaires' disease is not a communicable disease and we have recently discovered that the transmissible form of this disease - a spore-like cyst - is not appreciably produced in alveolar macrophages. We are characterizing this newly discovered developmental cycle by proteome and genome profiling (Proteomics and QRT-PCR), by identifying key stage specific regulators and regulated genes, and by mechanistic analysis of early events of invasion that abrogate signal transduction networks required for phagolysosome fusion and redirect the bacteria to a replication proficient endosome enveloped by the endoplasmic reticulum. We wish to know how super-virulent and metabolically dormant (asleep) cyst-like-forms are pre-programmed so as to activate upon contact with a host cell and through interactions with host cell proteins, promote invasion and then we wish to know what the "wake up call" is that activates the germination program to permit germination of cysts into vegetative replicating bacteria. Legionella is a model system for the study of obligate intracellular pathogens such as Chlamydia and Coxiella.

We are interested in the host-parasite interaction of H. pylori with the gastric mucosa.
The highly motile bacteria reside about 10 to 30 meters above the gastric epithelial cells and we wish to know how that stay within this zone. We have recently discovered these bacteria use pH taxis to orient in a pH gradient that is most acidic near the lumen and most alkaline near the epithelial cells. We also know that tactic signals also involve oxygen, hydrogen and urea. By understanding how these tactic signals are translated into staying in this optimal zone, we can build new therapeutics that essentially blind the bacteria and cause them to not survive. Antibiotic resistance is increasing at an alarming rate and within 15 years the "superbugs" (resistant to all antibiotics) will account for 15% of all human infections and contribute to high mortality. My laboratory has been involved in the study of drug resistance and in the development of new genomic/bioinformatic based strategies for identifying new microbial targets to aid the discovery of new therapeutics. We have identified the mode of action of a novel antiparasitic drug Nitazoxanide that is used world wide to treat parasitic infections caused by Entamoeba, Giardia, and Cryptosporidium. Mechanistic studies of this drug and others will lead to next generation therapeutics so critically needed to control infectious diseases. Also, checkout Canadian lab - microbiology.medicine.dal.ca/people/hoffman/ and genomics.medicine.dal.ca (DalGEN).

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