School of Medicine
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Professor of Pediatrics (Infectious Diseases) and of Microbiology and Immunology
Current Research and Scholarly Interests My laboratory studies how bacteria colonize our bodies for long periods of time, and how interactions between bacteria and the epithelial surfaces of the gastrointestinal tract and skin may lead to disease. Epithelial surfaces are the first barrier against infection, but they also where our bodies meet and co-evolve with the microbial world.. Several of our studies have focused on the epithelial junctions as a target for bacterial pathogens. The host epithelium uses its epithelial junctions to form a tight but dynamic barrier with an external surface that is inhospitable to microbial attachment, secretes anti-microbial compounds, and has a rapid rate of self-renewal. The balance in the microbe-epithelial relationship results in silent commensalism or symbiosis; an imbalance results in diseases ranging from acute bacterial invasive disease to chronic ulcers or carcinoma.
Our laboratory has developed novel microscopy applications such as quantitative 3D confocal microscopy, electron microscopy, time-lapse imaging, microinjection and micromanipulation to visualize the interaction of pathogens with epithelial cells in culture and in animal and human tissues. Many of out studies focus on the gastric pathogen Helicobacter pylori, but we have also expanded our investigations to include the intestinal pathogens Listeria monocytogenes and Salmonella enterica, and the skin pathogen and colonizer Staphylococcus aureus. I believe that elucidating how microbes communicate with and alter our epithelial cells at a molecular level will be important for finding novel therapeutic targets to control mucosal colonization and prevent invasive disease.
Using this perspective, we have uncovered several novel concepts of how bacteria colonize and breach our epithelial surfaces. For example, we discovered that Helicobacter pylori target the intercellular junctions, and in particular that the virulence factor CagA affects junction assembly and cell polarity. This confers H. pylori the ability to extract nutrients and grow directly on the epithelial surface. We also found that these properties of CagA have consequences for cellular transformation of the epithelium. For instance, we showed that H. pylori affect the activity and state of epithelial stem cells in the stomach by colonizing the epithelial surface deep in the gastric glands. This gland-associated population is essential for pathological inflammation and hyperplasia in animal models, and confers significant colonization advantages to the bacteria. Our Listeria research uncovered a new mechanism and site where bacteria can breach the gastrointestinal epithelial barrier to invade. We found that Listeria find their receptor for invasion at sites of epithelial senescence, where the epithelial junctions undergo dynamic turnover. To study Salmonella and H. pylori we have developed a human organoid model to study their interactions with human gut epithelium in vitro. To study Staphylococcus aureus pathogenesis, we have developed methods to visualize infection at the scale of a single bacterial microcolony using an organoid culture system of human keratinocytes and fibroblasts that grow into a 3D skin-equivalent. We recently identified several proteins at the eptithelial junctions as host factors involved in the pathogenesis of one of Staphylococcus aureus major toxins.
Ann M. Arvin
Lucile Salter Packard Professor of Pediatrics and Professor of Microbiology and Immunology
Current Research and Scholarly Interests Our laboratory investigates the pathogenesis of varicella zoster virus (VZV) infection, focusing on the functional roles of particular viral gene products in pathogenesis and virus-cell interactions in differentiated human cells in humans and in Scid-hu mouse models of VZV cell tropisms in vivo, and the immunobiology of VZV infections.
Helen M. Blau
The Donald E. and Delia B. Baxter Foundation Professor and Director, Baxter Laboratory for Stem Cell Biology
Current Research and Scholarly Interests Prof. Helen Blau's research area is regenerative medicine with a focus on stem cells. Her research on nuclear reprogramming and demonstrating the plasticity of cell fate using cell fusion is well known and her laboratory has also pioneered the design of biomaterials to mimic the in vivo microenvironment and direct stem cell fate. Current findings are leading to more efficient iPS generation, cell based therapies by dedifferentiation a la newts, and discovery of novel molecules and therapies.
Professor of Pathology and of Microbiology and Immunology and, by courtesy, of Chemical and Systems Biology
Current Research and Scholarly Interests Our lab uses chemical, biochemical, and cell biological methods to study protease function in human disease. Projects include:
1) Design and synthesis of novel chemical probes for serine and cysteine hydrolases.
2) Understanding the role of hydrolases in bacterial pathogenesis and the human parasites, Plasmodium falciparum and Toxoplasma gondii.
3) Defining the specific functional roles of proteases during the process of tumorogenesis.
4) In vivo imaging of protease activity
Assistant Professor of Medicine (Infectious Diseases) and of Microbiology and Immunology
Current Research and Scholarly Interests We study innate immunity.
Burt and Marion Avery Professor of Immunology
Current Research and Scholarly Interests We are intereseted in the interaction between the protozoan parasite Toxoplasma gondii and its mammalian host. We use a combination of molecular and genetic tools to understand how this obligate intracellular parasite can invade almost any cell it encounters, how it co-opts a host cell once inside and how it evades the immune response to produce a life-long, persistent infection.