Sarkis K. Mazmanian
Research Interests
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.
Symbiotic bacteria elaborate immunomodulatory molecules
which are recognized by host immune cells (dendritic cells),
and presented to T cells in order to mediate development of
the mammalian immune system.
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.
Recipient of the 2007 Young Investigator Award, Edward Mallinckrodt Foundation, 2008 Damon Runyon Cancer Foundation Rachleff Innovation Award, 2008 W.M. Keck Foundation Research Excellence Award, 2008 "Best Brains in Science under 40" Discover Magazine, 2008 Excellence in Teaching Award, Associated Student of the California Institute of Technology, 2009 Benirschke Scholar in Ulcerative Colitis Research, Crohn's and Colitis Foundation