Top-rated researchers from the far corners of the world come to the Mucosal Immunology and Biology Research Center (MIBRC). Founded by Dr. Allan Walker in the early 1990s, the facility formerly known as the Mucosal Immunology Lab houses seven principal investigators and two collaborators.
Dr. Alessio Fasano took over the leadership of the MIBRC in 2013 when he brought his team of international researchers from Maryland to Massachusetts. With post-doctoral researchers, lab managers, research assistants and support staff, the MIBRC group now comprises approximately 40 people.
Research in my lab is directed at understanding how immune responses to bacterial infection are influenced by host and environmental factors. Over the last 5 to 6 years, we have been characterizing the interactions between iron homeostasis and the response to infection.
We have made significant contributions to this area, particularly with respect to the effects of the mammalian iron transporter ferroportin on microbial growth and host innate immunity.
Recently, we have also started to analyze the effects of inflammation on iron metabolism. Our observations have provided mechanistic insights into the immunological consequences of disordered iron homeostasis and, conversely, into the effects of inflammatory diseases on iron handling.
The main focus of my laboratory centers on the bacterial pathogen Shigella flexneri, which causes a significant global health burden each year by causing millions of infections, predominantly in children under the age of five years in developing countries. Despite more than 50 years of effort, there is still no effective vaccine against this pathogen. While many aspects of the Shigella infection cycle have been investigated, a crucial gap in knowledge remains in the important steps in pathogenesis during early infection.
During research designed to develop a cholera vaccine in the late 1990s, I uncovered a toxin, zonula occludens, which causes diarrhea by loosening the tight junctions between enterocytes in the intestine, thus allowing intestinal permeability. Subsequently, our lab identified the protein zonulin, which controls this process. We have since established the role of zonulin in the pathogenesis of celiac disease and type 1 diabetes.
We are currently investigating the composition and changes in the gastrointestinal microbiota to help determine why some individuals with an inherited predisposition to celiac disease develop clinical disease while others do not. We are also investigating the role of the timing of gluten introduction to infants in the development of celiac disease and working to uncover a biomarker and to develop a diagnostic tool for gluten sensitivity.
Other current research projects include possible links between gluten-related disorders and conditions such as schizophrenia and Autism Spectrum Disorder in certain subgroups of patients. Our latest research includes a focus on how gut microbiota is related to the development of autoimmune disorders.
My laboratory studies polarity, epithelial morphogenesis and growth regulation in Caenorhabditis elegans. One of our objectives is to contribute to the understanding of the molecular basis of intestinal morphogenesis. C. elegans is a transparent roundworm whose internal organs are formed by different types of tubes constructed from distinct, yet simple, polarized epithelia. The simplicity of this organism when combined with its sophisticated genetic resources makes it a powerful tool to examine tubulogenesis.
We have recently identified a number of vesicle-associated proteins and lipids that are required for apicobasal plasma membrane domain and lumen foundation. Understanding organ development will advance our understanding of the pathogenesis of human diseases related to these organs, which in turn should lead to novel approaches for their diagnosis and treatment. Specifically, we hope that this work will translate into a better understanding of: (1) the still enigmatic link between the development of cancer and the disruption of polarity, cell shape and developmental genes, and (2) developmental diseases of internal organs and the vasculature.
The research interests of my laboratory are themed around gaining a better understanding of infectious and inflammatory diseases that target mucosal surfaces of the lung and digestive tract.
More specifically our group explores how bacterial pathogens, toxins, and allergens impact granulocyte (neutrophil and eosinophil) trans-epithelial migration, eicosanoid inflammatory mediator synthesis, and maintenance epithelial barrier integrity through engagement of innate immune pathways.
With a more thorough understanding of the mucosal barrier and its vulnerabilities, we will be able to develop therapeutics aimed at mucosal barrier fortification in the face of a diverse array of threats.
Research in my lab is focused on three areas: the effects of chronic intestinal helminth infection on concurrent infection with bacterial enteropathogens, the influence of early intestinal colonization with probiotic organisms on subsequent mucosal immune responses, and the effects of maternal gestational factors on the development of allergic disease in the offspring.
In each of these projects, we use a combination of in vitro and in vivo experiments to clarify the mechanisms that contribute to alterations in immune function. The overall goal of these studies is to understand basic principles in immunoregulation in the gut and to use this information to shed light on diseases in which intestinal immunity is disturbed.
My research efforts include defining the passive and active protective properties of human breast milk with regard to the protection from disease during the newborn period. I also study the development of human intestinal host defenses using human fetal organ cultures, cell lines, and xenograft transplant models. Specifically, my laboratory has reported that the human fetal epithelium responds inappropriately to both endotoxin and exotoxins, which helps to explain an increased incidence and severity of certain inflammatory and secretory diarrheas in this age group.
More recently, we have studied the effect of initial colonizing microbiota on the development of mucosal protective function and the mechanism of probiotics in this process. Until January 2013, I have been responsible for overseeing the Mucosal Immunology and Developmental Gastroenterology Laboratories as part of the Gastroenterology and Nutrition Division at MGHfC at Harvard Medical School, which is now the Mucosal Immunology and Biology Research Center, headed by Dr. Alessio Fasano.
My laboratory is centered around three major research programs: Mucosal inflammation, host-pathogen interactions, and cancer biology. The objective of the mucosal inflammatory program is to investigate the molecular mechanisms by which bacterial pathogens induce mucosal inflammation at sites of the intestinal and respiratory epithelium. This work is based on longstanding pathologic observations that attachment of an array of bacterial pathogens to epithelial surfaces is accompanied by recruitment of host defense cells, as manifested by neutrophil infiltration of the epithelium.
My laboratory is also centered on the study of host-pathogen interactions, and specifically the investigation of strategies used by enteric and respiratory pathogens to induce proinflammatory responses.
The third area of research in my laboratory is focused on cancer biology. My original interest in this field of study was cultivated by the observation that Salmonella is able to preferentially locate to sites of tumor growth (achieving tumor/normal tissue ratios of approximately 1,000:1). The ultimate goal of this work is to exploit Salmonella for the development of a new and robust class of multidrug resistance inhibitors designed as an adjuvant to chemotherapeutics for cancers that are known to express high levels of Pgp, such as colorectal cancers and breast cancer.
I am Director of the Genetics, Genomics and Molecular Biology Core of the Center for the Study of Inflammatory Bowel Diseases (CSIBD) at MGH and the Director for Information Systems for the Division of Gastroenterology at MGH. My laboratory has a long-standing interest in basic mechanisms controlling the mucosal immune system, intestinal barrier function and Inflammatory Bowel Diseases (IBD).
My current research interests focus on the mechanisms of IBD susceptibility genes in the regulation of the mucosal subspecifications of antigen-processing cells for microbial recognition in the intestine. Our laboratory has expertise in biochemical and cell biological methods and applies molecular biological approaches to the characterization of the mucosal immune system with particular focus on mechanisms of macrophage and dendritic cell innate immune function.
Recently, we have developed novel 3D and 4D imaging approaches to study membrane trafficking, antigen uptake, and cell migration in the mucosal immune system. Many of my post-doctoral fellows have gone on to establish their own laboratories studying different aspects of epithelial cell biology and mucosal immunology.