Effects Of Diet And Parasites On The Gut Microbiota Of Diverse Sub-Saharan Africans

ABSTRACT EFFECTS OF DIET AND PARASITES ON THE GUT MICROBIOTA OF DIVERSE SUB-SAHARAN AFRICANS Meagan A. Rubel Sarah A. Tishkoff 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

Effects of Diet and Parasites on The Gut Microbiota of Diverse Sub-Saharan Africans

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

Radiologist-supervised Transfer Learning

PurposeTo assess the potential of a transfer learning strategy leveraging radiologist supervision to enhance convolutional neural network-based (CNN) localization of pneumonia on radiographs and to further assess the prognostic value of CNN severity quantification on patients evaluated for COVID-19 pneumonia, for whom severity on the presenting radiograph is a known predictor of mortality and intubation.Materials and methodsWe obtained an initial CNN previously trained to localize pneumonia along with 25,684 radiographs used for its training. We additionally curated 1466 radiographs from patients who had a computed tomography (CT) performed on the same day. Regional likelihoods of pneumonia were then annotated by cardiothoracic radiologists, referencing these CTs. Combining data, a preexisting CNN was fine-tuned using transfer learning. Whole-image and regional performance of the updated CNN was assessed using receiver-operating characteristic area under the curve and Dice. Finally, the value of CNN measurements was assessed with survival analysis on 203 patients with COVID-19 and compared against modified radiographic assessment of lung edema (mRALE) score.ResultsPneumonia detection area under the curve improved on both internal (0.756 to 0.841) and external (0.864 to 0.876) validation data. Dice overlap also improved, particularly in the lung bases (R: 0.121 to 0.433, L: 0.111 to 0.486). There was strong correlation between radiologist mRALE score and CNN fractional area of involvement (ρ=0.85). Survival analysis showed similar, strong prognostic ability of the CNN and mRALE for mortality, likelihood of intubation, and duration of hospitalization among patients with COVID-19.ConclusionsRadiologist-supervised transfer learning can enhance the ability of CNNs to localize and quantify the severity of disease. Closed-loop systems incorporating radiologists may be beneficial for continued improvement of artificial intelligence algorithms

Durability of Protection Post–Primary COVID-19 Vaccination in the United States

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

Population structure of human gut bacteria in a diverse cohort from rural Tanzania and Botswana

Abstract 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

Single-Cell Analysis of the Plasmablast Response to Vibrio cholerae Demonstrates Expansion of Cross-Reactive Memory B Cells

ABSTRACT 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

Population Genetic Structure of Traditional Populations in the Peruvian Central Andes and Implications for South American Population History

Molecular-based characterizations of Andean peoples are traditionally conducted in the service of elucidating continent-level evolutionary processes in South America. Consequently, genetic variation among “western” Andean populations is often represented in relation to variation among “eastern” Amazon and Orinoco River Basin populations. This west-east contrast in patterns of population genetic variation is typically attributed to large-scale phenomena, such as dual founder colonization events or difffering long-term microevolutionary histories. However, alternative explanations that consider the nature and causes of population genetic diversity within the Andean region remain underexplored. Here we examine population genetic diversity in the Peruvian Central Andes using data from the mtDNA first hypervariable region and Y-chromosome short tandem repeats among 17 newly sampled populations and 15 published samples. Using this geographically comprehensive data set, we first reassessed the currently accepted pattern of western versus eastern population genetic structure, which our results ultimately reject: mtDNA population diversities were lower, rather than higher, within Andean versus eastern populations, and only highland Y-chromosomes exhibited significantly higher within-population diversities compared with eastern groups. Multiple populations, including several highland samples, exhibited low genetic diversities for both genetic systems. Second, we explored whether the implementation of Inca state and Spanish colonial policies starting at about ad 1400 could have substantially restructured population genetic variation and consequently constitute a primary explanation for the extant pattern of population diversity in the Peruvian Central Andes. Our results suggest that Peruvian Central Andean population structure cannot be parsimoniously explained as the sole outcome of combined Inca and Spanish policies on the region’s population demography: highland populations difffered from coastal and lowland populations in mtDNA genetic structure only; highland groups also showed strong evidence of female-biased gene flow and/or efffective sizes relative to other Peruvian ecozones. Taken together, these findings indicate that population genetic structure in the Peruvian Central Andes is considerably more complex than previously reported and that characterizations of and explanations for genetic variation may be best pursued within more localized regions and defined time periods