Immune-Microbiota Interplay in Intestinal Immune Homeostasis
Our lab is interested in understanding how the dynamic interplay between the intestinal immune system and the gut microbiota promotes intestinal immune tolerance, and contributes to the development and resolution of inflammatory bowel disease. Specifically, we are focused on understanding the cellular and molecular mechanisms that underlie the establishment and maintenance of immune homeostasis at mucosal surfaces.
The extraordinary ability of the immune system to discriminate between harmful and innocuous entities, and to tailor the response appropriately, has long preoccupied immunologists. Nowhere in the body is this challenge as great as at mucosal surfaces such as the intestine. Laden with harmless and beneficial microbes and viruses (the microbiota) that contribute to host health, such sites are also common entry routes for pathogens. The immune system is therefore charged with generating protective immunity against invasive agents and maintaining peaceful relationships with the resident microbiota. Understanding this phenomenon and leveraging this knowledge to develop improved therapeutics to treat inflammatory disease is the driving force of our lab.
The extraordinary ability of the immune system to discriminate between harmful and innocuous entities, and to tailor the response appropriately, has long preoccupied immunologists. Nowhere in the body is this challenge as great as at mucosal surfaces such as the intestine. Laden with harmless and beneficial microbes and viruses (the microbiota) that contribute to host health, such sites are also common entry routes for pathogens. The immune system is therefore charged with generating protective immunity against invasive agents and maintaining peaceful relationships with the resident microbiota. Understanding this phenomenon and leveraging this knowledge to develop improved therapeutics to treat inflammatory disease is the driving force of our lab.
Identification of microbial drivers of intestinal inflammation
Immune reactivity against the gut microbiota has long been recognized as a hallmark feature of IBD and many murine models of intestinal inflammation require the presence of a gut microbiota for development of disease. Despite this, very little is known about the microbes that drive pathogenesis during IBD. We are using a combination of immunological and microbiological approaches in gnotobiotic murine models of IBD to identify the microbial strains that shape the development and severity of intestinal inflammation, and the molecular mechanisms that underlie these interactions. By teasing apart the contributions of different microbes to the development and prevention of inflammation will allow more tailored targeting of the microbiota to treat IBD, helping to overcome the problems associated with current microbiota-based therapy, e.g. antibiotic treatment and faecal microbiota transplantation.
Control of CD4+ T cell fate
Upon activation CD4+ T cells become polarised such that they can mount an appropriate immune response to deal with the inciting stimulus. Despite a wealth of information with respect to the activation and differentiation processes of CD4+ T cells, there is still a dearth of precise details surrounding the decision point that leads to the development of pro-inflammatory or anti-inflammatory/ tolerogenic CD4+ T cell responses. Moreover, the microbial specificity of intestinal CD4+ T cells, and how that relates to function, is poorly defined. We are interested in delineating the reactivity of intestinal CD4+ T cells during health and active IBD, and understanding how the quantity and quality of these responses is regulated. More broadly, we are interested in understanding what makes a "successful" CD4+ T cell, i.e. what features of the cell or its activation allow it to successfully out-compete other cells with the same specificity.
Resolution of chronic intestinal inflammation
Treatment for IBD typically involves the use of anti-inflammatory agents that aim to quell the damaging inflammatory responses. While clinically efficacious, many patients do not respond or become non-responsive to therapy. We believe that efforts to actively promote resolution of disease, rather than simply blocking inflammation, may lead to more effective therapeutic approaches that provide long-term benefit but do not leave gaps in protective immunity. However, little is know about the cellular and molecular processes that orchestrate the resolution of chronic inflammation, particularly in situations like IBD, where the inflammatory stimulus (the microbiota) is never cleared. We are using a resolving model of chronic intestinal inflammation to probe the cellular and cytokine networks that control the initiation and execution of resolution, in addition to studying how the microbiota contributes to the promotion of resolution of perpetuation of inflammation.
Microbial pathways contributing to intestinal homeostasis and inflammation
Much of our understanding of how the immune system recognises and reacts to the gut microbiota is understood from the perspective of the immune cell alone, with little attention paid to the potential of the microbiota to play an active role in these interactions. Understanding how the microbiota stably engrafts in the intestine to regulate the outcome of interactions with the host immune system and using this knowledge to modify the function of the microbiota in a targeted and precise manner is an attractive approach to treat inflammatory disease. However, development of such strategies is hampered by our lack of understanding of such processes. We are interested in gaining a more complete understanding of the microbial pathways that dictate the nature of microbiota interactions with the host and facilitate the long term fitness of microbes in the inflamed intestine.
Other interests
While we have a particular interest in the problems described above, we are fundamentally interested in understanding all aspects of host-microbiota interactions in the intestine, and unraveling the rules that mediate the homeostatic relationship between these two complex systems. For example, the lab is currently attempting to better understand how non-haematopoietic aspects of the intestinal cellular network, such as fibroblasts, interact with the gut microbiota to contribute to the pathogenesis of IBD.