Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and ...subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.
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•Microbiome loss impairs antibody response in subjects with low pre-existing immunity•Antibiotics treatment leads to enhanced inflammatory signatures in the blood•Loss of secondary bile acids is linked to AP-1/NR4A and inflammasome activation•Integrative analysis reveals divergent mechanisms of microbiome influence on immunity
Antibiotic-use-induced alterations to the gut microbiome can adversely affect immunogenicity and responses to influenza vaccination in humans.
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the ...single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03’s potential as an epigenetic adjuvant.
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•Single-cell map of the epigenomic and transcriptomic landscape to vaccination•Vaccination stimulates persistent epigenomic changes in myeloid cells•Identification of epigenomically distinct subsets of monocytes•Adjuvanted influenza vaccine stimulates epigenomic remodeling of antiviral immunity
The epigenomic and transcriptional response to influenza vaccination provides insights into the immunological changes in monocytes that influence antiviral immunity, including a role for the adjuvant AS03 in bolstering antiviral immunity to unrelated viruses such as Zika and Dengue.
Invasive populations often experience founder effects: a loss of genetic diversity relative to the source population, due to a small number of founders. Even where these founder effects do not impact ...colonization success, theory predicts they might affect the rate at which invasive populations expand. This is because secondary founder effects are generated at advancing population edges, further reducing local genetic diversity and elevating genetic load. We show that in an expanding invasive population of the Asian honey bee (Apis cerana), genetic diversity is indeed lowest at range edges, including at the complementary sex determiner, csd, a locus that is homozygous-lethal. Consistent with lower local csd diversity, range edge colonies had lower brood viability than colonies in the range centre. Further, simulations of a newly-founded and expanding honey bee population corroborate the spatial patterns in mean colony fitness observed in our empirical data and show that such genetic load at range edges will slow the rate of population expansion.
Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help ...to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
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•Integrative analysis of orthogonal data on response to vaccination•Strong association between plasma metabolomics and PBMC transcriptomics•Sterol metabolism integrates cellular and humoral responses•Metabolic phenotype, such as inositol phosphate metabolism, influences immune outcome
An integrated metabolic response underlies the immune response to shingles vaccine in humans.
Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that ...mechanistic target of rapamycin (mTOR)–dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103⁺ DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b⁺ DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (TH2) to neutrophilic TH17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation.
The modes through which individuals disperse prior to reproduction has important consequences for gene flow in populations. In honey bees (
sp.), drones (males) reproduce within a short flight range ...of their natal nest, leaving and returning each afternoon within a narrow mating window. Drones are assumed to return to their natal nests as they depend on workers to feed them. However, in apiaries, drones are reported to regularly make navigation errors and return to a non-natal nest, where they are accepted and fed by unrelated workers. If such a "drone drift" occurred in wild populations, it could facilitate some further degree of dispersal for males, particularly if drones drift into host nests some distance away from their natal nest. Here, we investigated whether drone drift occurs in an invasive population of the Asian honey bee (
). Based on the genotypes of 1462 drones from 19 colonies, we found only a single drone that could be considered a candidate drifter (~0.07%). In three other colonies, drones whose genotypes differed from the inferred queen were best explained by recent queen turnover or worker-laying. We concluded that drone drift in this population is low at best, and
drones either rarely make navigation errors in wild populations or are not accepted into foreign nests when they do so. We therefore confirm that drone dispersal distance is limited to the distance of daily drone flights from natal nests, a key assumption of both colony density estimates based on sampling of drone congregation areas and population genetic models of gene flow in honey bees.
To describe the self-advocacy experiences of women from underrepresented groups who have advanced breast or gynecologic cancer.
To be eligible for the study, participants had to self-identify as ...vulnerable, which was defined as a member of a group considered at risk for poor cancer outcomes and underrepresented in clinical research.
This descriptive, longitudinal, qualitative study consisted of one-on-one interviews of women within three months of an advanced breast or gynecologic cancer diagnosis.
10 participants completed 25 interviews. The average age of participants was 60.2 years (range = 38-75 years). Three major themes emerged: (a) speaking up and speaking out, (b) interacting with the healthcare team, and (c) relying on support from others.
Women with advanced cancer who are from underrepresented groups self-advocated in unique ways, learning over time the importance of how to communicate their needs and manage their healthcare team. Future research should incorporate these findings into tailored self-advocacy interventions.
Systemic immunity is stringently regulated by commensal intestinal microbes, including the pathobiont Candida albicans. This fungus utilizes various transcriptional and morphological programs for ...host adaptation, but how this heterogeneity affects immunogenicity remains uncertain. We show that UME6, a transcriptional regulator of filamentation, is essential for intestinal C. albicans-primed systemic Th17 immunity. UME6 deletion and constitutive overexpression strains are non-immunogenic during commensal colonization, whereas immunogenicity is restored by C. albicans undergoing oscillating UME6 expression linked with β-glucan and mannan production. In turn, intestinal reconstitution with these fungal cell wall components restores protective Th17 immunity to mice colonized with UME6-locked variants. These fungal cell wall ligands and commensal C. albicans stimulate Th17 immunity through multiple host pattern recognition receptors, including Toll-like receptor 2 (TLR2), TLR4, Dectin-1, and Dectin-2, which work synergistically for colonization-induced protection. Thus, dynamic gene expression fluctuations by C. albicans during symbiotic colonization are essential for priming host immunity against disseminated infection.
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•C. albicans cells locked into UME6-on or -off states fail to prime immunogenicity•Forced oscillations of UME6 support C. albicans-induced Th17 immunogenicity•Intestinal fungal β-glucan and mannan stimulate systemic Th17 immunogenicity•Th17 immunogenicity requires signaling via multiple pattern recognition receptors
Intestinal colonization by commensal microbes, including the fungal pathobiont Candida albicans, primes protective immunological changes throughout the body. Shao et al. show that Th17 immunity primed by commensal C. albicans requires dynamic oscillations in expression of the transcriptional regulator UME6, which controls fungal morphology and virulence.
Black women face poor maternal health outcomes including being over 3 times more likely to die from pregnancy complications than White women. Yet the lived experience of how these women self-advocate ...has not been clearly explored. The goal of this cross-sectional qualitative study was to describe the lived experiences of Black women advocating for their needs and priorities during the perinatal period.
Between January and October of 2022, we recruited Black women from obstetric clinics, research registries, and community advocacy groups who were either in their third trimester of pregnancy or within a year postpartum. Participants completed one-on-one interviews describing their experiences of self-advocacy. These data were analyzed using descriptive content analysis approaches that summarized women's experiences by iteratively creating major themes and subthemes that encapsulate their self-advocacy descriptions.
Fifteen Black women completed interviews. Major themes and subthemes describing women's experience of self-advocacy were the following: (1) carrying a burden with subthemes of having to be good and easy, not trusting health care information and providers, and being dismissed; (2) building comfort with health care providers with subthemes of trusting I have a good provider, comfort in knowing they understand, and wanting low-touch, high-concern care; and (3) advocating for my child and myself when I need to with subthemes of going with the flow, becoming informed, pushing to ask questions, and balancing being proactive and pushy.
Women reported self-advocating mainly due to experiences related to the burdens associated with not trusting providers and health care information. These findings provide clarity to how women carefully balance between ensuring their health is taken seriously while not jeopardizing their health or that of their newborn. This study offers promising directions to support Black women in advocating for their perinatal health care needs and values.
Abstract Cost-effective and scalable synthetic matrices that support long-term expansion of human pluripotent stem cells (hPSCs) have many applications, ranging from drug screening platforms to ...regenerative medicine. Here, we report the development of a hydrogel-based matrix containing synthetic heparin-mimicking moieties that supports the long-term expansion of hPSCs (≥20 passages) in a chemically defined medium. HPSCs expanded on this synthetic matrix maintained their characteristic morphology, colony forming ability, karyotypic stability, and differentiation potential. We also used the synthetic matrix as a platform to investigate the effects of various physicochemical properties of the extracellular environment on the adhesion, growth, and self-renewal of hPSCs. The observed cellular responses can be explained in terms of matrix interface-mediated binding of extracellular matrix proteins, growth factors, and other cell-secreted factors, which create an instructive microenvironment to support self-renewal of hPSCs. These synthetic matrices, which comprise of “off-the-shelf” components and are easy to synthesize, provide an ideal tool to elucidate the molecular mechanisms that control stem cell fate.
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