Research at the Mucosal Immunology Laboratory
Within the mission of the Mucosal Immunology Laboratory, each of the nine principal investigators and the director work independently in their own areas of interest, and collaboratively with other investigators. Please click on the name of each investigator in the sidebar at left for a detailed description of that person's research.
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.
My laboratory studies epithelial morphogenesis and growth regulation in Caenorhabditis elegans. One of our objectives is to contribute to the understaning 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 make it a powerful tool to examine tubulogenesis. We have recently identified a number of cytoskeletal genes that are required to build the apical/luminal and basolateral membranes of the intestine and other tubular organs. 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.
A major focus of our work is to understand processes that lead to mucosal barrier breach in the context of inflammation and disease within the lung and the digestive tract. Insults with the potential to compromise the mucosal barrier include microbial toxins that target or exploit the polarized mucosal epithelium or pathogens and their products that instigate inflammation resulting in recruitment of neutrophils that breach epithelial barriers and cause tissue damage. Neutrophils serve an important role in innate immunity charged with eradicating dangerous pathogens. Owing to the non-specific nature of the neutrophil arsenal, neutrophil infiltration of the mucosa can be detrimental to host tissue if sufficient resolution is not achieved following neutrophil mobilization. Destructive neutrophilic breach of the mucosa can occur in the airway and the gut in response to pathogenic infection or as a result of autoimmune or auto-inflammatory disease. Examples of such illness include cystic fibrosis, pneumonia, ARDS, & COPD in the lung and IBD & certain enteric infections in the gut. We have identified a neutrophil chemo-attractant that is critical to directing neutrophil breach of mucosal barriers. This molecule is an eicosanoid called hepoxilin A3 and it is produced by mucosal epithelial cells of both the lung and gut. Efforts are underway to better understand the genes involves in the synthesis of hepoxilin A3 by epithelial cells and to develop strategies to interfere with hepoxilin A3 function. Such approaches may prove efficacious in combating overzealous inflammation marked by neutrophil breach of mucosal barriers progressing to severe tissue damage, which characterizes numerous ailments of the lung and digestive tract. Ultimately a more thorough understanding of the mucosal barrier and its vulnerabilities will serve to drive development of therapeutics aimed at mucosal barrier fortification in the face of a diverse array of threats.
Hai Ning Shi, DVM, PhD
Associate Professor of Pediatrics
My research interests are focused regulation of mucosal immunity in the gastrointestinal tract. We use both in vivo and in vitro approaches to elucidate the mechanisms by which an intestinal helminth infection modulates intestinal inflammation induced by pathogenic and non-pathogenic enteric bacteria. Using our recently established helminth-bacterial co-infection mouse model, we demonstrated that infection with the intestinal helminth parasite, Heligmosomoides polygyrus, results in the development of exacerbated intestinal inflammation in mice infected with the Gram-negative bacterial enteropathogen Citrobacter rodentium, a mouse pathogen similar to human EPEC. We are currently addressing the idea that the exacerbating effect on intestinal inflammation is the consequence of helminth induced (1) modulation of T cell function to a phenotype that promotes proinflammatory responses, in part by impairing intestinal epithelial barrier function, and (2) alterations in macrophage phenotype and function that compromise the ability to eliminate translocated bacteria. Another area of our research focuses on how intestinal colonization of probiotics and/or treatment with prebiotics early in life influences the development and regulation of host innate and adaptive immune responses. This research will provide greater insight into how intestinal microorganisms may alter the regulatory mechanisms of mucosal immunity, which may be instrumental in the establishment of more effective and safer preventive and therapeutic approaches for the treatment of immune mediated disorders and for the design of effective mucosal vaccines. The third area of my research is directed at clarifying the role of maternal factors during gestation in the development of immunity and the induction of allergic diseases in the early life of the offsprings. We ultimately seek to elicit information that may help protect children from developing food allergy and enhance their immune capacity to react to antigenic challenges.
My primary responsibilities at Massachusetts General Hospital involve overseeing the Mucosal Immunology and Developmental Gastroenterology Laboratories at Building 114 MGH-East as part of the Gastroenterology and Nutrition Division at MGHfC at Harvard Medical School. These laboratories have five principal investigators, six postdoctoral fellows and two graduate students who study oral tolerance, gut inflammation and microbial-epithelial "crosstalk." 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.
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 she investigate 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.
The Reinecker laboratory has a long standing interest in basic mechanisms controlling the mucosal immune system, intestinal barrier function and Inflammatory Bowel Diseases (IBD). Dr. Reinecker is an Associate Professor of Medicine at Harvard Medical School and an Associate Immunologist at MGH. Dr. Reinecker is the 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. 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. The laboratory has expertise in biochemical and cell biological methods and applies molecular biological approaches to the characterization of the mucosal immune system with particular focusÊ on mechanisms of macrophage and dendritic cell innate immune function.Ê Recently, Dr. Reinecker has developed novel 3D and 4D imaging approaches to study membrane trafficking, antigen uptake and cell migration in the mucosal immune system. Many of Dr. Reinecker's post doctoral fellows have gone on to establish their own laboratories studying different aspects of epithelial cell biology and mucosal immunology.