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Background African populations provide a unique opportunity to interrogate host-microbe co-evolution and its impact on adaptive phenotypes due to their genomic, phenotypic, and cultural diversity. We integrate gut microbiome 16S rRNA amplicon and shotgun metagenomic sequence data with quantification of pathogen burden and measures of immune parameters for 575 ethnically diverse Africans from Cameroon. Subjects followed pastoralist, agropastoralist, and hunter-gatherer lifestyles and were compared to an urban US population from Philadelphia. Results We observe significant differences in gut microbiome composition across populations that correlate with subsistence strategy and country. After these, the variable most strongly associated with gut microbiome structure in Cameroonians is the presence of gut parasites. Hunter-gatherers have high frequencies of parasites relative to agropastoralists and pastoralists. Ascaris lumbricoides , Necator americanus , Trichuris trichiura , and Strongyloides stercoralis soil-transmitted helminths (“ANTS” parasites) significantly co-occur, and increased frequency of gut parasites correlates with increased gut microbial diversity. Gut microbiome composition predicts ANTS positivity with 80% accuracy. Colonization with ANTS, in turn, is associated with elevated levels of TH1, TH2, and proinflammatory cytokines, indicating an association with multiple immune mechanisms. The unprecedented size of this dataset allowed interrogation of additional questions—for example, we find that Fulani pastoralists, who consume high levels of milk, possess an enrichment of gut bacteria that catabolize galactose, an end product of lactose metabolism, and of bacteria that metabolize lipids. Conclusions These data document associations of bacterial microbiota and eukaryotic parasites with each other and with host immune responses; each of these is further correlated with subsistence practices.

Background Gut microbiota from individuals in rural, non-industrialized societies differ from those in individuals from industrialized societies. Here, we use 16S rRNA sequencing to survey the gut bacteria of seven non-industrialized populations from Tanzania and Botswana. These include populations practicing traditional hunter-gatherer, pastoralist, and agropastoralist subsistence lifestyles and a comparative urban cohort from the greater Philadelphia region. Results We find that bacterial diversity per individual and within-population phylogenetic dissimilarity differs between Botswanan and Tanzanian populations, with Tanzania generally having higher diversity per individual and lower dissimilarity between individuals. Among subsistence groups, the gut bacteria of hunter-gatherers are phylogenetically distinct from both agropastoralists and pastoralists, but that of agropastoralists and pastoralists were not significantly different from each other. Nearly half of the Bantu-speaking agropastoralists from Botswana have gut bacteria that are very similar to the Philadelphian cohort. Based on imputed metagenomic content, US samples have a relative enrichment of genes found in pathways for degradation of several common industrial pollutants. Within two African populations, we find evidence that bacterial composition correlates with the genetic relatedness between individuals. Conclusions Across the cohort, similarity in bacterial presence/absence compositions between people increases with both geographic proximity and genetic relatedness, while abundance weighted bacterial composition varies more significantly with geographic proximity than with genetic relatedness.

Gene expression differences are shaped by selective pressures and contribute to phenotypic differences between species. We identified 964 copy number differences (CNDs) of conserved sequences across three primate species and examined their potential effects on gene expression profiles. Samples with copy number different genes had significantly different expression than samples with neutral copy number. Genes encoding regulatory molecules differed in copy number and were associated with significant expression differences. Additionally, we identified 127 CNDs that were processed pseudogenes and some of which were expressed. Furthermore, there were copy number-different regulatory regions such as ultraconserved elements and long intergenic noncoding RNAs with the potential to affect expression. We postulate that CNDs of these conserved sequences fine-tune developmental pathways by altering the levels of RNA.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Contemporary African populations possess myriad genetic and phenotypic adaptations to diverse diets, varying climates, and infectious diseases. Most microbiome studies to date have focused on primarily European and Asian populations in urban, industrialized settings. By comparison, relatively little is known about traditional African gut microbiomes, and the range of variation they contain. Many African populations are undergoing substantial changes because of rapid globalization, easier access to hygienic resources and medications, shifts away from traditional lifestyle, and increased exposure to processed diets high in sugars and fats. By characterizing microbiome variation among sub-Saharan African populations using metagenomic sequencing, we can better understand differential response to diseases and environmental factors in producing physiological adaptations. Furthermore, by extending microbiome sampling across a range of traditional African populations in multiple countries, it may be possible to trace subsistence transition with changes in settlement and diet, and interrogate how these are shaped by industrialization. In this dissertation, I describe the gut microbiomes of populations practicing agropastoralism, hunting and gathering, and pastoralism in three African countries: Botswana, Cameroon, and Tanzania. To do this, I used amplicon and shotgun sequencing to characterize microbial genomes and annotate their functions. I combined this microbial data with extensive phenotype and ethnographic data. With this dataset, I detected gut microbial taxa associated with subsistence strategy, sex, geography, and host genetics. I demonstrated that the degree of industrialization in these populations correlated with enrichment of functional pathways involved in the metabolism of xenobiotics and industrial pollutants. Moreover, I found that the gut microbiome has no association with HIV infection, but is highly predictive of multiple gastroenteric parasite infections within Cameroonians. Parasite infection and microbiome composition were, in turn, associated with Th-2 proinflammatory cytokines that are produced during helminthiasis. My research captures microbiota and taxa that are rare or absent from microbiomes of industrialized populations and expands the definition of normal variation within the human gut microbiome. My dissertation identifies multiple factors affecting microbiome composition and works towards generating a more holistic interpretation of the structure and function of human gut microbiota, and their potential associations with human physiology and adaptation.

We characterized the acute B cell response in adults with cholera by analyzing the repertoire, specificity, and functional characteristics of 138 monoclonal antibodies (MAbs) generated from single-cell-sorted plasmablasts. We found that the cholera-induced responses were characterized by high levels of somatic hypermutation and large clonal expansions. A majority of the expansions targeted cholera toxin (CT) or lipopolysaccharide (LPS). Using a novel proteomics approach, we were able to identify sialidase as another major antigen targeted by the antibody response to Vibrio cholerae infection. Antitoxin MAbs targeted both the A and B subunits, and most were also potent neutralizers of enterotoxigenic Escherichia coli heat-labile toxin. LPS-specific MAbs uniformly targeted the O-specific polysaccharide, with no detectable responses to either the core or the lipid moiety of LPS. Interestingly, the LPS-specific antibodies varied widely in serotype specificity and functional characteristics. One participant infected with the Ogawa serotype produced highly mutated LPS-specific antibodies that preferentially bound the previously circulating Inaba serotype. This demonstrates durable memory against a polysaccharide antigen presented at the mucosal surface and provides a mechanism for the long-term, partial heterotypic immunity seen following cholera. IMPORTANCE Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with Vibrio cholerae . Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different V. cholerae serotypes and the likely impact of prior enterotoxigenic Escherichia coli exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts. Cholera is a diarrheal disease that results in significant mortality. While oral cholera vaccines are beneficial, they do not achieve equivalent protection compared to infection with Vibrio cholerae . Although antibodies likely mediate protection, the mechanisms of immunity following cholera are poorly understood, and a detailed understanding of antibody responses to cholera is of significance for human health. In this study, we characterized the human response to cholera at the single-plasmablast, monoclonal antibody level. Although this approach has not been widely applied to the study of human bacterial infection, we were able to uncover the basis of cross-reactivity between different V. cholerae serotypes and the likely impact of prior enterotoxigenic Escherichia coli exposure on the response to cholera, as well as identify novel antigenic targets. In addition to improving our understanding of the repertoire and function of the antibody response to cholera in humans, this study has implications for future cholera vaccination efforts.

The durability of immune responses after COVID-19 vaccination will drive long-term vaccine effectiveness across settings and may differ by vaccine type. To determine durability of protection of COVID-19 vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S) following primary vaccination in the United States, a matched case-control study was conducted in three cohorts between 1 January and 7 September 2021 using de-identified data from a database covering 168 million lives. Odds ratios (ORs) for developing outcomes of interest (breakthrough SARS-CoV-2 infection, hospitalization, or intensive care unit admission) were determined for each vaccine (no direct comparisons). In total, 17,017,435 individuals were identified. Relative to the baseline, stable protection was observed for Ad26.COV2.S against infections (OR [95% confidence interval (CI)], 1.31 [1.18–1.47]) and hospitalizations (OR [95% CI], 1.25 [0.86–1.80]). Relative to the baseline, protection waned over time against infections for BNT162b2 (OR [95% CI], 2.20 [2.01–2.40]) and mRNA-1273 (OR [95% CI], 2.07 [1.87–2.29]) and against hospitalizations for BNT162b2 (OR [95% CI], 2.38 [1.79–3.17]). Baseline protection remained stable for intensive care unit admissions for all three vaccines. Calculated baseline VE was consistent with published literature. This study suggests that the three vaccines in three separate populations may have different durability profiles.