Biasing immunological development with early life microbial colonization
生命早期微生物定植导致免疫发育偏向
基本信息
- 批准号:10730933
- 负责人:
- 金额:$ 44.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-08 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAfricanAmericanAmphibiaAnimalsAutoimmune DiseasesBacteriaBiological AssayBiological MetamorphosisBiological ModelsBody TemperatureChronicClinicalCommunitiesCustomDevelopmentDiseaseDisease OutcomeDoseEducationEducational ModelsEmbryoEquilibriumExposure toFusariumGene Expression RegulationGenerationsGenetic TranscriptionGerm-FreeGnotobioticHealthHomeostasisHumanHypersensitivityImmuneImmune responseImmune systemImmunityImmunologicsImmunologyIndividualInfectionInflammatoryInvestmentsIrritable Bowel SyndromeJournalsLarvaLifeMeasuresMethodsMicrobeModelingMolecularMusMycosesObesityOutcomePatternPhysiologyPredispositionPreventive MedicineRanaResearchResearch DesignResourcesRoleSignal TransductionSpecificityStudentsSystemSystems DevelopmentTestingTimeTrainingTraining ProgramsVertebratesWorkXenopusXenopus laevisbiomedical scientistcomparativeequilibrium modelfunctional genomicsgene panelhatchinghost microbiomehost-microbe interactionshuman pathogenimmune functionimmune stimulantimmune system functionimmunoregulationimprovedinnovationmicrobialmicrobial colonizationmicrobiomemicrobiotamodel developmentmodel organismnano-stringnovelpathogenpathogenic funguspermissivenessprophylacticresponsestudent participationsymbionttooltranslational medicineundergraduate research experienceundergraduate studentxenopus development
项目摘要
Project Summary
Microbial colonization during development impacts microbiome assembly, immune system functioning, and
health outcomes later in life. The central hypothesis of this proposal is that immune equilibrium is
established in early development and education of the immune system can be biased by hysteresis from
previous host encounters with microbes. The timing and sequence of encounter (i.e., microbial exposure
priority effects) may tolerize or promote host immune responsiveness. A novel gnotobiotic (but not axenic/germ-
free) model host, the African Clawed Frog, Xenopus laevis, is ideal for probing critical windows and stimulants
of immune system development. We invoke Krogh’s principle for this research on education of the immune
system in amphibians because “for a large number of problems there will be some animal of choice, or a few
such animals, on which it can be most conveniently studied” (Krogh 1929, The American Journal of Physiology).
Early developmental manipulations are easier in a frog than in a mouse, and immune regulatory patterns in
amphibians, like mouse and other vertebrates, are analogous to human responses. Amphibians are also ideal
for study of fungal infections emerging in humans because of more permissive body temperatures and clear
survival readouts. The specific aims are: (1) Immunological Hysteresis Effects on Fusarium Infection and
(2) - Immunological Hysteresis Effects on the Microbiome. In Aim 1 we will establish the developmental
window for immune education by microbial exposure. We will then compare stimulation by live microbes including
individual pathogens, mutualists, or high diversity natural communities, as well as microbe-associated molecular
patterns (MAMPs), and host damage signals. We will observe disease outcome with respect to novel or repeat
exposure to a clinical dose of Fusarium applied at a climax developmental stage and quantify immune gene
transcriptional responses. We will thus test factors by which immunological hysteresis tolerizes the host toward
unresponsiveness or primes the host toward responsiveness to the fungal pathogen. This aim will further
establish the Xenopus model system for development and immunology as well as emerging fungal pathogens
of humans and provide an innovative method for indicating potentially conserved immune gene regulation in
amphibians and humans. In Aim 2 we will investigate the impacts of immunological hysteresis on the
assemblage of the host microbiome, and measure the potential direct effects of microbial partners on pathogens
in culture to determine whether these symbionts are facilitated or inhibited by immunological hysteresis. This aim
will engage the training of advanced undergraduate students (trainees) in a Course-based Undergraduate
Research Experience (CURE). The aims will be accomplished by leveraging the Xenopus gnotobiotic system,
Fusarium infection model, custom NanoString immune gene panel, and inclusion of undergraduate trainees in
research using the CURE. The collaborative research team has state-of-the-art facilities and interdisciplinary
expertise spanning comparative immunology, the microbiome, and infectious pathogens.
项目总结
项目成果
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