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MIBRC Research

Principal Investigators:

Bobby Cherayil, MD

Alessio Fasano, MD

Verena Göbel, MD

Bryan Hurley, PhD

Hai Ning Shi, DVM, PhD

W. Allan Walker, MD

Collaborators:

Beth McCormick, PhD

Hans-Christian Reinecker, MD

 

Research at MIBRC

Mucosal immunology is the study of the surfaces of the mucosa—the thin layer of tissue that lines the body cavities in the gastrointestinal, respiratory and urogenital tracts. The mucosa provides the first line of defense in the body’s fight against a range of pathogenic microbes.

The mucosal immune system employs a sophisticated response to invaders as it distinguishes pathogens from beneficial flora and harmless dietary antigens. When this sophisticated system is unable to distinguish pathogens from innocuous antigens, diseases such as food allergies, inflammatory bowel disease, and celiac disease can result.

By studying the complex molecular mechanisms of mucosal immunology, researchers are making discoveries that are leading to the development of vaccines, adjuvant and immunotherapeutics to treat disorders arising from these conditions.

The Intestine and the External Environment

The intestine is a major site for the interaction between the host and the external environment. In particular, the intestinal mucosa is continually exposed to a wide variety of non-pathogenic and pathogenic microbes and their toxins. Both immune and non-immune protective mechanisms are involved in the host’s interaction with these environmental stimuli.

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Mouse Epithelium: MIBRC researchers use a variety of in vivo and in vitro approaches to examine intestinal mucosal responses to luminal antigens that trigger the development of intestinal inflammatory responses that can lead to chronic inflammatory disease.

The central component of the interaction between luminal microbes and intestinal host defense is the epithelium juxtaposed between the external and internal environments. The enterocyte has been demonstrated to play an active role in intestinal host defense. For example, in response to microbial colonization or enterotoxin and endotoxin stimulation, the enterocyte can upregulate the transcription of inflamamatory cytokines and membrane surface molecules to more effectively participate in mucosal defense.

Currently, we have a limited understanding of how enterocyte immune and inflammatory responses are regulated and what their specific contributions are to the intestinal mucosal host defense in health and disease. Nonetheless, this area of investigation is extremely important, and many opportunities exist to make breakthroughs that could ultimately lead to new strategies for the prevention and treatment of infectious intestinal diseases as well as autoimmune disorders. Our principal investigators are working on different aspects of these questions.

The Gut’s Epithelium in Intestinal Barrier Function

The collective effort of individual investigators is focused on the role of the gut epithelium in intestinal barrier function, and how interactions with immune and inflammatory cells (neutrophils and macrophages) via cytokine release influence the epithelial barrier’s response to microbial luminal stimuli.

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Figures 1 and 2 show the interaction of invasive microorganisms and/or their enterotoxins with enterocytes that result in epithelial/lymphoid or epithelial/nerve cell communications. Molecular, cellular and in vivo approaches are used to study the mechanisms and consequences of this interaction of microbes, enterotoxins, endotoxins and probiotics with coloncytes as they relate to both inflammation and maintenance of the tight junctions and the intestinal barrier.

Newly established human fetal primary and conditionally immortalized cell lines and human xenograft approaches have been characterized. MIBRC researchers will use these to define the molecular mechanism(s) of a developmental epithelial response to bacterial exo- and endotoxin stimuli.