Project 2: Epigenetic ontogeny of vaccine response, susceptibility to respiratory infectious disease and asthma

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SUMMARY – Project 2 (PR2) Early life microbial exposures can shape an individual’s basal immune state influencing acute responses to infections, vaccines and responses to environmental allergens. Perinatal microbial exposures are known to influence immune ontogeny and are linked to rising rates of allergy and asthma, yet mechanisms remain poorly defined. Colonisation of the mucosae by microbiota, vaccinations and systemic infections all modify immune ontogeny, but a mechanistic understanding of the combinatorial interactions of these events in the early life course, and their resulting programming effects on immune development in early life (IDEAL) are lacking. Project 2 (PR2) will investigate epigenetic mechanisms as a basis for understanding microbially-mediated programming of IDEAL. A growing body of work highlights an important role for epigenetic regulation of the genome in both central and peripheral immune cells following vaccination and infection. Dynamic changes in epigenetic modifications at gene enhancers and promoters in innate cells are mechanistically linked to pathogen recognition receptor (PRR) signalling. These mechanisms therefore bridge the microbial environment, host genome and immune ontogeny. Early life microbial exposures are a complex construct considering the broad scope of interactions and factors to consider. Yet our collaborators in the Clinical Core (CC; Lead Pichichero) have demonstrated reproducibly that some children display a phenotype of low production of protective antibody (Ab) levels to routine vaccinations with concomitant low cellular immune memory (low vaccine responders, LVR), whilst others exhibit robust protective immunity (high vaccine responders, HVR). In addition to this, some children are prone to recurrent respiratory infections (infection prone, IP) whilst others with similar pathogen burden are resilient (non-infection prone, NIP). These phenotypic subgroups will be capitalized upon as latent variables that reflect the construct of microbially-mediated immune programming through a latent class analysis. The overall effort will define trajectories of mucosal and systemic (e.g., immune ontogeny and microbiome across our IDEAL Meta Cohort (IMC) comprised of four diverse longitudinal childhood cohorts in relation to VR, IP and asthma. Epigenome-wide association analysis will identify methylation-sensitive genes that characterize trajectories of IDEAL. We posit that these phenotypes and sub-phenotypes of IDEAL contribute to the development of childhood illness and will therefore identify methylation-sensitive genes associated with IDEAL trajectories that predict endotypes and sub-phenotypes of VR, IP and asthma. We consider endotypes are likely to have distinct pathophysiology mechanisms and that epigenetic biomarkers of microbially-mediated immune programming can provide early detection as well as novel targets for precision interventions. Outcomes from PR2 will include enhanced mechanistic understanding of early immune programming, knowledge gains regarding genomic elements/pathways contributing to endotypes of VR, IP and asthma, prognostic biomarkers, and novel targets for preventive interventions.