Biomedical Base
Harvard Clinical Nutrition Research Center
Biomedical Base
Immunology and Microbiology
Following are the primary investigators of this theme and a brief discussion of their work.
Dr. Walker continues as the PI for the Center and an Investigator in the HCNRC renewal. The major goal of Dr. Walker’s laboratory is to study nutritional effects on the development of mucosal immune function as it pertains to clinical disease states. A considerable effort has been directed at the role of breast milk in the development of mucosal host defenses within the newborn intestine. Currently these efforts have been directed at: (1) the effect of breast milk ingestion on active mucosal antibody production by the newborn; (2) the mechanisms by which breast milk provides passive protection in the neonatal intestine against foreign antigen absorption, bacterial/toxin binding and uptake by enterocytes and (3) the trophic effects (e.g., effect of growth factors in breast milk) on gastrointestinal maturation. In addition to breast milk immunology, Dr. Walker uses human small intestinal models (an H4 human primary fetal small intestinal cell line, organ cultures, fetal small intestine, and surgical resection small intestine and a xenograft transplant model for fetal small intestine). These techniques are used to study protective nutrient effects (probiotics, prebiotics, omega-3-fatty acids, glutamine, etc.) on the development of intestinal host defenses against pathogens and potentially harmful antigens. To accomplish these goals, he extensively uses the Cell Biology Core and collaborates with Drs. Nanthakumar, Cherayil, Nagler-Anderson, Sanderson, Pothoulakis, Meydani and Podolsky. Another major aim of this laboratory is the study the uptake of foreign antigens and bacterial toxins in the developing intestine. The uptake of these noxious molecules is immature during the perinatal period and may be the basis for immune-medicated inflammation and toxic diarrheal disease in young infants. When newborn animals are starved for short time periods (12-24 hours), the mucosal barrier to antigens and bacterial toxins is more permeable. Thus, enteric nutrition may be an important factor in the delayed maturation of the mucosal barrier.
Harry Pothoulakis
Dr. Pothoulakis joins the HCNRC renewal as new Investigator. He was attracted to the Center as a mentor of a P/F recipient to study the role of leptin in the inflammation. Dr. Pothoulakis is an internationally recognized authority on the role of neuropeptides in gut inflammation, particularly inflammation caused by chlostrial toxins. He shares a program project grant to study microbial epithelial interaction with Drs. Walker, McCormick, Cherayil, Nanthakumar and Newburg. He has developed a center for the study of neuropeptides involved in satiety on gut inflammation and infection. This interest has resulted in another P/F application (2005-06) to examine ghrelin in inflammation. Dr. Pothoulakis currently occupies laboratory space at MGH-East to study these projects.
Biographical sketch forthcoming.
Steve Calderwood
Dr. Calderwood continues as an Investigator in the HCNRC renewal. He is the Division Chief of the Infectious Disease Unit of the Medical Services at MGH. His research interests are to define the pathogenesis of Vibrio cholera infections and the mechanisms by which invasive bacteria, Salmonella, and Shigella, translocate across the intestine to cause infectious diarrhea and sepsis. His laboratory has four major areas of interest: 1) Analyzing the genes and gene products involved in the molecular pathogenesis of bacterial infection, particularly diarrhea caused by gram-negative pathogens such as Vibrio cholerae and enterohemorrhagic E. coli (EHEC), and the regulation of these genes in response to environmental stimuli in vitro, in animal models, and in human infection; 2) Development of live, attenuated strains of V. cholerae as vaccine vectors to deliver heterologous antigens to the common mucosal immune system. 3) He also has a NIH-funded program of International Collaborations in Infectious Disease Research, in conjunction with the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, to analyze human mucosal immune responses following natural V. cholerae infection, to analyze gene expression in V. cholerae directly in human samples, and to use human immune responses following cholera to identify bacterial genes uniquely expressed during human infection; 4) He uses a number of non-vertebrate hosts, including plants, Caenorhabditis elegans, and wax moth caterpillars, to model microbial-host interactions. His interest within the HCNRC is to define the role of malnutrition in these processes.
Beth Mccormick
Dr. McCormick continues as an Investigator in the HCNRC renewal application. She has trained a number of postdoctoral fellows with a strong interest in the nutritional effect on the pathogenesis of enteric infections. Dr. Karen Mumy, a postdoctoral fellow, plans to submit a P/F application on the role of polyamines in gut inflammation in 2006. Her research efforts are as follows: Current research activities are, at the moment, exclusively focused on bench research. This research is funded by an NIH RO1 and a PO1 award and is focused on dissecting the molecular mechanisms by which enteric pathogens induce mucosal inflammatory responses. Ultimately, results obtained from both of these research projects will provide valuable insight into novel mechanisms of bacterial pathogenesis as well as establish clues for developing novel treatment strategies for active inflammation found in patients with infectious, allergic, and idiopathic colitis. The RO1 funded project entitled “Intestinal Inflammation Orchestrated by Pathogens” is an extension of her previous work, which demonstrated that intestinal epithelial cells respond to lumenal pathogens, such as S. typhimurium, by releasing distinctive proinflammatory chemoattractants, which sequentially orchestrate PMN movement across the intestinal epithelium. She has found that S. typhimurium-intestinal epithelial cell interactions induce the epithelial synthesis and polarized basolateral release of the potent PMN chemokine, interleukin-8 (IL-8). Currently, she has identified the first such proinflammatory mediator called pathogen elicited epithelial chemoattractant (PEEC), which we have recently identified as the eicosanoid hepoxilin A3. Thus, the general goal of the RO1 funded project is to sort out the molecular and cellular mechanisms by which S. typhimurium induces the epithelial secretion of hepoxilin A3. She is also the Principal Investigator of Project 3 on a newly funded NIH PO1 grant. Project 3 is entitled “Shigellosis. Role of the intestinal epithelium” and is focused on how Shigella flexneri are able to coordinate the mucosal immune response, which leads to an intense inflammatory reaction in humans characterized by bacillary dysentery. The research goals proposed are directed at (i) understanding the nature of the species dependency of Shigella with the human intestine, and (ii) elucidating the molecular basis by which Shigella foster acute infectious colitis. The newest project in her lab, sponsored by the Cystic Fibrosis Foundation, focuses on bacterial infections of the lung, another mucosal surface. Lung disease as a consequence of bacterial infection in many situations is marked by severe inflammation, particularly the accumulation of large numbers of neutrophils in the lumenal space along the respiratory tract. It is currently unclear what bacterial factors can trigger this response and exactly how the neutrophils are directed to the site of infection. Understanding this process is the broad long-term objective of her work.
Frederick Ausubel
Dr. Ausubel continues as an Investigator and Core Director in the HCNRC renewal application. He has been an enormous asset to the Center. His Molecular Biology Core (renamed the Genomics Core in the new application) provides extensive consultation and teaching to Investigators and Associate Investigators. With his strong research interest in microorganisms, he has established extensive collaborations with Drs. Calderwood, Walker, McCormick, Sanderson, Tompkins and Yarmush. His laboratory studies the molecular basis of bacterial pathogenesis in plants and animals. They are particularly interested in elucidating aspects of pathogenesis that are similar irrespective of the pathogen and the host. The plant model system that we are studying is the pathogenic interaction between Pseudomonas syringe and the small flowering plant Arabidopsis thaliana.. Their long-term goal in this model is to elucidate the mechanisms whereby the plant and pathogen recognize each other and how the recognition signals are transduced causing the transcriptional activation of virulence genes in the pathogen and defense-related genes in the host. In addition to this work with the plant pathogen P. syringe, he has developed a novel model system designed to identify previously unknown virulence genes in the human pathogen Pseudomonas aeruginosa. Dr. Ausubel has identified a P. aeruginosa clinical isolate, strain PA14, that is infectious in a mouse burn model as well as in the flowering plants Arabidopsis thaliana (referred to as “Arabidopsis” for simplicity)and lettuce and in the insects Galleria mellonella (greater wax moth) and Drosophila melanogaster. In addition, PA14 kills the nematode Caenorhabditis elegans and various yeast and fungi including Saccharomyces cerevisiae. This expertise will expand our basic research capacity in the area of development of innate immunity and will provide access by Center members to genomics techniques.
Denise Faustman
Dr. Faustman continues as an Investigator in the HCNRC renewal. A P/F award in 1996 helped launce her current research in type I diabetes. Dr. Faustman has a strong background in molecular immunology. She has been attracted to the Center by virtue of PFP funding, access to Cores, and a strong relationship with Dr. David Schoenfeld as the Biostatitian used to help define molecular markers for Type 1 diabetes. This relationship and the PFP funding has led to publications and independent grant support. Her laboratory is strongly devoted to the study of autoimmmunity with a particular emphasis in Type 1 diabetes. The overlap between nutrition and autoimmunity is immense. For example, it has consistently been observed that the incidence of diabetes in offsprings of breast feeding mother’s is lower. Also the simultaneous exposure of newborns to cow’s milk is associated with earlier onset and a higher frequency of Type 1 diabetes. The fact that the NIH is supporting large multi-center trials attempting to defer diabetes onset with oral insulin and this research emphasis again suggests a pivotal role of “nutrition” and exposure in diabetes course. Similar pathogenic mechanism appears to exist for autoimmune diseases such as rheumatoid arthritis, lupus, etc. The Immunobiology Lab’s current program in autoimmunity includes: (1) Mapping by predominantly biochemical analysis, the intracellular antigen processing events leading to defective T cell education, (2) isolating new immune response genes in the HLP/MHC region as contributors to autoreactivity, (3) analyzing a point mutation in the high risk MHC genetic region of the NOD autoimmune mouse that changes the relative levels of immune response genes such as LMP and TAP, and (4) attempts in transplantation models to prevent autoimmunity or recurrent autoimmunity by either correcting faulty T cell education or gene therapy of donor islets
David Newburg
Dr. Newburg continues as an Investigator in the HCNRC renewal. In August 2004, he joined the Developmental Gastroenterology Laboratory at MGH-East as a Glycobiologist and has assumed responsibilities for the Cell Biology Core as Core B Director in the renewal application. He has also joined the Executive Committee of the HCNRC. Dr. Newburg has previously collaborated with Drs. Walker and Nanthakumar, but now adds a new dimension to the Center by providing an expertise in glycobiology which dovetails with numerous Center Investigators’ interests. Early malnutrition accompanied by diarrhea, the most common environmental insult that can limit critical phases of an infant’s development, is significantly less frequent among breastfed infants than those fed artificial formula. Previously, this had been attributed to the nutritional superiority of human milk and the presence of antibodies. Dr. Newburg’s research program has discovered previously unrecognized protective glycans (complex carbohydrate structures, i.e., glycoconjugates and oligosaccharides) in human milk that inhibit binding of pathogens (bacteria, viruses, and toxins) to the intestinal cells of the infant, thereby lowering the rate of infection. Ultimately, increased understanding of the role of glycans in the pathogenesis of diarrhea and other diseases will allow investigator to identify individuals and populations at high risk and to prevent and treat these diseases by providing exogenous glycans upon weaning, thereby protecting the world’s children from the diarrhea-associated malnutrition that limits their development.
Pei-Ra Ling
Dr. Ling joins the HCNRC as a new Investigator in the renewal application She is Co-Director of the Laboratory of Nutrition/Infection at the BIDMC. Her research interests are in the field of nutrition and cytokine physiology, particularly in cytokine signaling and its alteration by nutrient manipulation. Omega-3 fatty acids, medium chain triglycerides, and structured lipids, composed of long and medium chain fatty acids have been important substrates investigated using kinetic measures of protein, fat, and carbohydrate metabolism with both radio- and stable isotopes. More recently techniques of molecular biology including northern and western blots, immuoprecipitation and immuoblotting have been increasing employed through collaboration with Dr. David Newburg in the Cell Biology Core at MGH-East. These studies will be done in the Genomics Core in the new research period. Experimental works performed both in clinical studies of sepsis and injury and small animal models of the systemic inflammatory response employing endotoxin, interleukin-1, interleukin-6 and tumor necrosis factor to produce the inflamed state. She plans to use the Mass Spectrometry, Cell Biology and Genomics Cores
Bobby Cherayil
Dr. Cherayil joins the HCNRC renewal as an new Investigator. Research in his laboratory is focused on the molecular mechanisms involved in the pathogenesis of Salmonella infection. He is interested in two aspects of pathogenesis - the role of pattern recognition receptors expressed by intestinal epithelial cells and macrophages in the innate immune response to the organism, and the influence of changes in cellular iron metabolism and the mammalian iron transporter ferroportin 1 (FPN1) on intracellular bacterial survival. Iron is a micronutrient that is essential for both Salmonella and its mammalian host. In preliminary experiments, carried out in collaboration with the laboratory of Dr. Marianne Wessling-Resnick of the Harvard School of Public Health, they have found that altered FPN1 expression has a significant effect on the ability of Salmonella to survive and multiply within cells. They are currently exploring the mechanism behind this effect and its implications for clinical disorders of FPN1 expression and function.
Glenn Furuta
Dr. Furuta, a former Associate Investigator and P/F awardee, joins the HCNRC renewal as a new Investigator. His primary interest is the mechanisms of food allergy in the pediatric patient. His previous publications have led to therapeutic approaches to the treatment of eosinophilic esophagitis. His research is as follows. Dr. Furuta seeks to elucidate mechanisms that eosinophils participate in gastrointestinal health and disease. The major aim of his current work is to understand the role of eosinophil derived granule proteins, in particular major basic protein (MBP), on intestinal inflammatory processes. To that end, he has examined the impact of these specific proteins on resident cells of the gastrointestinal tract. As a part of our work, he found that eosinophil derived major basic protein induced a phenotypic change in mast cells stimulating mast cell derived TNF-alpha and serotonin release. In addition, we demonstrated that major basic protein stimulates IL-8 release from human intestinal fibroblasts. Currently, he is determining the impact of MBP on intestinal barrier function. Ultimately, he hypothesizes that interactions between eosinophils and resident cells of the gut contribute to both health and disease particularly to food allergy. He is also studying the role of eosinophils in clinical disease, particularly GERD at the GCRC at CH. Ultimately, he anticipates that the data derived from the combination of the basic and clinical studies will lead to the elucidation of mechanisms of eosinophilic food allergic gastrointestinal diseases and establishment of novel therapeutic agents.
Biographical sketch forthcoming.
Daniel Podolsky
Dr. Podolsky continues as an Investigator in the HCNRC renewal. Research in Dr. Podolsky’s laboratory focuses on three basic areas of relevance to IBD and nutritional influences on this condition. 1) His laboratory has a long-standing program to characterize the role of goblet cells in the colonic epithelium. Recent work in Podolsky’s laboratory have provided potentially important new insights into goblet cell function. His laboratory has cloned a distinctive peptide designated intestinal trefoil factor (ITF) which is specifically expressed normally in abundance by the goblet cell population in the small intestine and colon. In addition to providing a vehicle to delineate the molecular basis of goblet cell differentiation and gene expression recent studies have suggested that this peptide secreted in conjunction with mucin glycoproteins play a critical role in sustaining the integrity of the mucosal barrier and facilitating repair following mucosal injury. These studies are relevant to the role of prebiotics and probiotics in IBD and goblet cell mucus release. These include collaborations with Drs. Nagler-Anderson, Walker and McCormick. 2) In a second area of research, Dr. Podolsky has had a longstanding effort to define the peptide growth factors expressed by intestinal epithelial cells and their relative contributions to regulation of epithelial cell proliferation and commitment to differentiation. His laboratory first demonstrated the expression of the key growth regulatory peptides TGFa and TGFb by the epithelium and characterized the coordinate interrelationship between their expression and function in regulating epithelial turnover. In these studies he collaborates with Drs. Walker, Sanderson, and Newburg. 3) Finally, in the past three years, the Podolsky laboratory has been at the forefront of efforts exploring the role of the intestinal epithelial cells in innate immune responses in the gut. He demonstrated the presence of Toll-like receptors and subsequently NOD proteins and their role in mediating epithelial responses to commensal (probiotics) and invasive enteric bacteria. Current efforts focus on the mechanisms of action of these cell surface and intra-cellular receptors. A parallel study on the development of toll-like receptors and microbial epithelial crosstalk in the developing human intestine as it pertains to protective nutrients has lead to a collaboration between Drs. Podolsky and Sanderson, Newburg and Walker.
Katia Karalis
Dr. Karalis joins the HCNRC renewal as a new Investigator. She is a M.D./Ph.D. pediatric endocrinologist who collaborates with Dr. Pothoulakis in defining the role of corticotrophin-releasing hormone in the regulation of leptin expression in inflammatory states which was a P/F application in the HCNRC. This work has lead to funding from the Crohn’s Colitis Foundation and will be the basis for a RO1 application in the fall. This interaction with the HCNRC through the P/F mechanism has stimulated Dr. Karalis’ interest as a neuroendocrinolgist in the role of food ingestion and leptin release and its potential as a propagator of inflammation.
Biographical sketch forthcoming.
Simin Meydani
Dr. Meydani joins the HCNRC renewal as a new Investigator. She has a major interest in nutrition and immune function. She heads the Nutritional Immunology Laboratory at the USDA Center for Aging at Tufts New England Medical Center. The overall goal of Nutritional Immunology Laboratory (NIL) is to determine the relationship between nutrition and immune function and the prevention of immune-related diseases in the elderly. The research objectives of NIL are based upon the central hypothesis that nutritional status, and thereby nutritional interventions, have a strong regulating effect on the immune system of the elderly through regulation of oxidative stress- sensitive signal transduction and gene expression. Aging is associated with dysregulation of the immune response, which contributes to an increased incidence of infectious, inflammatory, and neoplastic diseases. Changes in both T cells and macrophages contribute to this age-associated immune response dysregulation. The NIL investigates the role of dietary components and their interactions with other environmental factors in age-associated changes of the immune and inflammatory responses. Research looks to reverse and/or delay the onset of these immunologic and age-related changes by appropriate dietary modifications and to determine the molecular mechanisms by which antioxidant and prooxidant nutrients modulate immune cell functions. The experimental approaches utilized by the laboratory extend from molecular and cellular mechanisms of nutrient-induced immune enhancement to the clinical and public health implications of these findings in developed and developing countries
Megan Murray
Dr. Murray joins the HNCRC renewal as a new Investigator. She is trained in internal medicine and infectious disease and has recently received a DSc from the HSPH. She has a longstanding interest in tuberculosis prevention based on work done in Thailand and Kenya. She has submitted a new P/F proposal (Type II) for the 2005-2006 competition to determine the role of iron in the spread of TB. She represents an established investigator who has been attracted to nutrition research through the HCNRC.