| NSF Org: |
IOS Division Of Integrative Organismal Systems |
| Recipient: |
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| Initial Amendment Date: | April 11, 2013 |
| Latest Amendment Date: | February 15, 2017 |
| Award Number: | 1253278 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
purnima bhanot
IOS Division Of Integrative Organismal Systems BIO Directorate for Biological Sciences |
| Start Date: | April 15, 2013 |
| End Date: | March 31, 2018 (Estimated) |
| Total Intended Award Amount: | $921,012.00 |
| Total Awarded Amount to Date: | $1,221,012.00 |
| Funds Obligated to Date: |
FY 2015 = $300,000.00 FY 2017 = $300,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
201 PRESIDENTS CIR SALT LAKE CITY UT US 84112-9049 (801)581-6903 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
15 N Medical Drive East Salt Lake City UT US 84112-8930 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): |
Cross-BIO Activities, Symbiosis Infection & Immunity, EPSCoR Co-Funding |
| Primary Program Source: |
01001516DB NSF RESEARCH & RELATED ACTIVIT 01001718DB NSF RESEARCH & RELATED ACTIVIT |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
Mammals are home to a vast consortium of commensal bacteria that help shape and maintain host health. While some resident microbes have beneficial consequences to the host, others are detrimental. Pathogenic and commensal bacteria share many of the same molecular motifs, making it unclear how the host immune system discriminates between beneficial and harmful bacterial species. Vertebrates possess a unique gene family, the major histocompatibility complex (MHC),that allows for activation of a tailored immune response toward a specific microbe. The fundamental function of the MHC gene locus is to allow the immune system to discriminate between "self" and "non-self" tissue, thus allowing the immune system to destroy microbial invaders, while preventing the immune system from attacking cells of the animal's own body. However, the investigators propose an additional, thus far un-appreciated role for the MHC: that a major driving force in the evolution of the MHC, beyond its long-known roles in animal "self" recognition and eradication of pathogens, is the need for animals to maintain a homeostatic relationship with their commensal microbial communities. This project will test this novel hypothesis using genetic and molecular approaches coupled with microbiota transfers into germfree mice. These studies have the potential to reveal how microbial communities are constructed within the host and to identify novel principles by which the host and microbes communicate. If the MHC is proven to govern the assembly of commensal communities, then animal "self" will need to be redefined to include not just the host animal itself, but also the animal's commensal microbiota. Educational goals of this project include research training for undergraduate, graduate and postdoctoral students. In addition, the investigator and her students will work with staff of a local natural history museum to create a summer science camp that teaches middle school children about their own commensal microbiota.
PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Virtually all animals must co-exist with microorganisms. In many cases, bacterial association has influenced the evolution and development of multiple animal species. Mammals are no different as they are residence to a consortium of bacterial, archeal and viral species. Recent studies have implicated certain bacterial members of the microbiota in normal development, function of the immune system and susceptibility or protection from multiple diseases. Therefore, the composition of the microbial community can have profound influences on the development and health of the host. Humans have a high level of inter-personal variation of microbial communities between individuals. While environment and diet are key factors in explaining this variability, it is becoming clear that host genotype is a fundamental determinant of microbial community assembly, however little was known about what genes were an important determinant of microbiota assembly.
Bacterial organisms, whether pathogenic or commensal, share many of the same molecular motifs that are recognized by innate animal systems to activate immunity. It remains unclear how animal hosts are able to discriminate between pathogenic and benign bacterial species or how tolerance to the commensal microbiota is actively maintained. Mammalian immune systems have the capacity to process and present specific proteins from bacteria, viruses and fungi. This provides the advantage of being able to use species-specific antigens in order to discriminate friend from foe, however this concept has never before been tested. The ability to process and present specific proteins from foreign entities relies on a highly polymorphic loci called the major histocompatibility complex (MHC). Investigations performed in our lab demonstrated that this gene loci is an important determinant of microbiota composition.
Intellectual Merit
It has been appreciated for decades that many organisms on this planet rely on symbiotic relationships to survive and thrive. Similarly, mammals harbor a vast consortium of commensal organisms that have only recently begun to be appreciated as playing an integral role in mammalian development. Because symbiotic bacteria have been associated with mammals since their inception, we propose that a major driving force in the evolution of the mammalian immune system has been the need to maintain homeostatic relationships with commensal bacteria and thus our microbiota is as much a part of our ‘self’ as our own genome encoded proteins. The role for MHC in microbiota-host interactions has never before been tested. If our hypotheses are proven correct, the results of the studies herein will transform long-standing ideas about the function and evolution of mammalian immunity through the testing of the following novel concepts:
1) Current dogma suggests that MHC presentation of microbial antigens results in onlyimmunity, however we propose that mucosal MHC provides an antigen specific means to induce toleranceto commensal bacteria and therefore represents a primary means to assemble microbial communities.
2) The current paradigm is that increased MHC diversity increases the hosts ability to eliminatepathogens, however we propose that increased MHC diversity within the intestine will permit a wider variety of commensal microbial communities to persistwithin the host.
This work has provided an additional explanation for why MHC has been maintained as a polymorphic locus and has provided in depth insight into how complex microbial communities are formed.
Broader Impacts
This grant has supported the training, growth and development of multiple individuals including a postdoctoral fellow that has now begun his own laboratory based on the results of these studies, graduate students and technicians. Importantly, we were able to extend these analysis to middle school children through a hands-on summer science camp that let learn about microbes on their bodies, work with animals, see eukaryotic cells and culture some of their own microbes.
Last Modified: 07/30/2018
Modified by: June Round
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