Sarkis K. Mazmanian
Evolutionary Mechanisms of Host-Bacterial Symbiosis during Health and Disease
Immunologic imbalances underlie many human diseases. Protection from autoimmune disorders, resistance to infections and the control of cancers require the proper functioning of the immune system. Fortunately, our immune system is not alone in this struggle. The human body represents a scaffold upon which multitudes of commensal species build residence, creating a diverse ecosystem with members of five of the six kingdoms of life. Mechanisms which mediate the interdependent and complex interactions within this super-organism, as well as their influences on human health, are almost entirely unknown. Our laboratory focuses on examining the processes which govern the development of the mammalian immune system, with the goals of understanding how symbiotic bacteria actively contribute to the critical balance between health and disease.
It has been appreciated for several decades that mammals display developmental defects of lymphoid tissues in the absence of bacterial colonization. Mostly, these defects have been observed in the immune responses of the gastrointestinal tract, where the greatest numbers and diversity of bacteria are found. As hundreds of different species permanently reside in the mammalian intestine, no single organism has been experimentally shown to correct these processes. Our work has demonstrated that not only do the immune deficiencies in the absence of bacterial colonization extend to the entire systemic immune response, but further identifies a specific molecule of a single commensal species which is both required and sufficient to direct host immune maturation. We have shown that during colonization of animals with the ubiquitous gut microorganism, Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and physical development of the immune system. Furthermore, it appears that this process is necessary for the overall health of the host, as immune pathologies are observed in the absence this bacterial signal. Thus it appears that humans may have an evolutionary requirement for the specific immunomodulatory direction provided by symbiotic bacteria. Our research provides experimental validation that directly extends to the "hygiene hypothesis" concept that relates the gastrointestinal flora to the underlying development of human disease.
The laboratory focuses on three major areas of study:
(1) Identify the molecular components of the host immune system which recognize and respond to the immunomodulatory signals of symbiotic bacteria.
(2) Define the cellular and molecular mechanisms which mediate protection to immune pathologies such as colitis.
(3) Explore the possibility of harnessing the beneficial effects provided by symbiotic bacteria for the development of therapies against immune-mediated disorders.
Identify the molecular components of the host immune system which recognize and respond to the immunomodulatory signals of symbiotic bacteria.
Over the past decade, many investigators have focused considerable research into molecules of the innate immune response to infections by pathogenic organisms. These Pattern Recognition Receptors (PRRs), most notably the Toll-Like Receptors (TLRs), represent a signaling mechanism by the immune system against harmful antigens. However, our mucosal and epithelial surfaces are replete with commensal organisms which are immunologically tolerated. Molecules like PSA, synthesized by symbiotic microbes, provide the host with signals alternate to that of inflammation elicited by TLR ligands. The molecular machinery which mediates these anti-inflammatory responses is unknown. We are currently working to identify the receptor and signaling pathways contained within immune cells which respond to the immunomodulatory activities of symbiotic bacteria. We intend to use biochemical, genetic and genomic techniques, as well as animal models, to characterize the molecular conversation between bacteria and host during symbiosis.
Define the cellular and molecular mechanisms which mediate protection to immune pathologies such as colitis.
The mammalian immune system has evolved an elaborate mechanism to delete or suppress inflammation against self antigens, the details of which have been extensively studied for decades. The mechanisms by which a host controls responses against encountered, non-pathogenic molecules, such as commensal bacteria, food and inhaled antigens, remains less defined. We are interested in understanding why and how mammals tolerate commensal bacteria and what happens when this usually beneficial relationship is disturbed. We employ an animal model of colitis whereby inflammatory responses are directed against commensal bacteria, resulting in the onset of intestinal pathology and disease (wasting) in laboratory animals. Treatment with PSA and colonization with B. fragilis completely protect animals from colitic disease, indicating that this molecule is involved in establishing immunological homeostasis of the gut during symbiosis. Through the use of various immunologic and bacteriologic methods, we plan to extend our studies to investigate the molecular mechanisms by which the immune system adapts to tolerate foreign antigens. Perhaps genetic defects in this pathway predispose individuals to inflammatory diseases. Characterization of these processes, the cell types and molecules involved, may provide an understanding for the basis of various human disorders including asthma and Inflammatory bowel disease (IBD) which appear to result from a defect in the immune systems ability to adequately (un)respond to encountered non-self molecules.
Explore the possibility of harnessing the beneficial effects provided by symbiotic bacteria for the development of therapies against immune-mediated disorders.
Research conducted over 4 decades ago documented that germ-free animals display defects in the ability to fight infections by pathogenic bacteria and viruses. The immunologic explanations for these findings have remained entirely undescribed. Our work provides an opportunity for mechanistic validation to these observations. We wish to determine if colonization with symbiotic bacteria, which direct host immune fitness, provides resistance to challenge by bacterial and viral agents. Having developed a model system which allows control of the maturation state of immune responses provides a powerful and unique approach toward understanding resistance to pathogenic infections. The use of genetic, cell biological, biochemical and genomic technologies will characterize the genesis of immune responses to pathogens and may prove invaluable in designing therapies to target multiple classes of infections.