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. Multiomics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.
Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutininspecific antibody production and changes in the size and character of hemagglutininreactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus. IMPORTANCE Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs).Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalkreactive, as well as to head-reactive, MBCs. Our findings provide experimental
Larus gull species have proven adaptable to urbanization and due to their generalist feeding behaviors, they provide useful opportunities to study how urban environments impact foraging behavior and host-associated microbiota. We evaluated how urbanization influenced the foraging behavior and microbiome characteristics of breeding herring gulls (Larus argentatus) at three different colonies on the east coast of the United States. Study colonies represented high, medium and low degrees of urbanization, respectively. At all colonies, gulls frequently foraged at landfills and in other urban environments, but both the use of urban environments and gull foraging metrics differed with the degree of urbanization. Gulls at the more urban colonies used urban environments more frequently, showed higher rates of site fidelity and took shorter trips. Gulls at less urban colonies used a greater diversity of habitat types and foraged offshore. We observed high microbial diversity at all colonies, though microbial diversity was highest at the least urban colony where gulls used a wider variety of foraging habitats. This suggests that gulls may acquire a wider range of bacteria when visiting a higher variety of foraging sites. Our findings highlight the influence of urban habitats on gull movements and microbiome composition and diversity during the breeding season and represent the first application of amplicon sequence variants, an objective and repeatable method of bacterial classification, to study the microbiota of a seabird species.
Several vaccines are approved in the United States for seasonal influenza vaccination every year. Here we compare the impact of repeat influenza vaccination on hemagglutination inhibition (HI) titers, antibody binding and affinity maturation to individual hemagglutinin (HA) domains, HA1 and HA2, across vaccine platforms. Fold change in HI and antibody binding to HA1 trends higher for H1N1pdm09 and H3N2 but not against B strains in groups vaccinated with FluBlok compared with FluCelvax and Fluzone. Antibody-affinity maturation occurs against HA1 domain of H1N1pdm09, H3N2 and B following vaccination with all vaccine platforms, but not against H1N1pdm09-HA2. Importantly, prior year vaccination of subjects receiving repeat vaccinations demonstrated reduced antibody-affinity maturation to HA1 of all three influenza virus strains irrespective of the vaccine platform. This study identifies an important impact of repeat vaccination on antibody-affinity maturation following vaccination, which may contribute to lower vaccine effectiveness of seasonal influenza vaccines in humans
Highlights d Longitudinal analysis of Ebola survivor reveals long-lasting IgM/IgG/IgA diversity d Despite undetectable virus, an EBOV-specific IgM suggests occult viral persistence d Antibody affinity and immunodominant sites associated with EVD resolution are revealed d Sites in C terminus of GP1 and GP2 are promising therapeutic and vaccine targets
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